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Dr Lisiane Meira

Lecturer in DNA Damage and Ageing
+44 (0)1483 686449
13A AY 04

Academic and research departments

School of Biosciences and Medicine.



Research interests

My teaching

Courses I teach on

My publications


Polycarpou E, Meira LB, Carrington S, Tyrrell E, Modjtahedi H, Carew MA (2013) Resveratrol 3-O-d-glucuronide and resveratrol 42-O-d-glucuronide inhibit colon cancer cell growth: Evidence for a role of A3 adenosine receptors, cyclin D1 depletion, and G1 cell cycle arrest, Molecular Nutrition and Food Research 57 (10) pp. 1708-1717
Scope: Resveratrol is a plant-derived polyphenol with chemotherapeutic properties in animal cancer models and many biochemical effects in vitro. Its bioavailability is low and raises the possibility that the metabolites of resveratrol have biological effects. Here we investigate the actions of resveratrol 3-O-d-glucuronide, resveratrol 42-O-d-glucuronide, and resveratrol 3-O-d-sulfate on the growth of colon cancer cells in vitro. Methods and results: The growth of Caco-2, HCT-116, and CCL-228 cells was measured using the neutral red and MTT assays. Resveratrol and each metabolite inhibited cell growth with IC50 values of 9.8-31 ¼M. Resveratrol caused S phase arrest in all three cell lines. Resveratrol 3-O-d-glucuronide and resveratrol 42-O-d-glucuronide caused G1 arrest in CCL-228 and Caco-2 cells. Resveratrol 3-O-d-sulfate had no effect on cell cycle. Growth inhibition was reversed by an inhibitor of AMP-activated protein kinase (compound C) or an adenosine A3 receptor antagonist (MRS1191). The A3 receptor agonist 2Cl-IB-MECA inhibited growth and A3 receptors were detected in all cell lines. The resveratrol glucuronides also reduced cyclin D1 levels but at higher concentrations than in growth experiments and generally did not increase phosphorylated AMP-activated protein kinase. Conclusion: Resveratrol glucuronides inhibit cell growth by G1 arrest and cyclin D1 depletion, and our results strongly suggest a role for A3 adenosine receptors in this inhibition. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Calvo JA, Meira LB, Lee CY, Moroski-Erkul CA, Abolhassani N, Taghizadeh K, Eichinger LW, Muthupalani S, Nordstrand LM, Klungland A, Samson LD (2012) DNA repair is indispensable for survival after acute inflammation., J Clin Invest. 122 (7) pp. 2680-2689 American Society for Clinical Investigation
More than 15% of cancer deaths worldwide are associated with underlying infections or inflammatory conditions, therefore understanding how inflammation contributes to cancer etiology is important for both cancer prevention and treatment. Inflamed tissues are known to harbor elevated etheno-base (µ-base) DNA lesions induced by the lipid peroxidation that is stimulated by reactive oxygen and nitrogen species (RONS) released from activated neutrophils and macrophages. Inflammation contributes to carcinogenesis in part via RONS-induced cytotoxic and mutagenic DNA lesions, including µ-base lesions. The mouse alkyl adenine DNA glycosylase (AAG, also known as MPG) recognizes such base lesions, thus protecting against inflammation-associated colon cancer. Two other DNA repair enzymes are known to repair µ-base lesions, namely ALKBH2 and ALKBH3; thus, we sought to determine whether these DNA dioxygenase enzymes could protect against chronic inflammation-mediated colon carcinogenesis. Using established chemically induced colitis and colon cancer models in mice, we show here that ALKBH2 and ALKBH3 provide cancer protection similar to that of the DNA glycosylase AAG. Moreover, Alkbh2 and Alkbh3 each display apparent epistasis with Aag. Surprisingly, deficiency in all 3 DNA repair enzymes confers a massively synergistic phenotype, such that animals lacking all 3 DNA repair enzymes cannot survive even a single bout of chemically induced colitis.
Mendes MM, Darling AL, Meira L, Lanham-New SA (2014) Vitamin D status and body composition in UK Caucasian and South Asian postmenopausal women: results from the DFINES II study, PROCEEDINGS OF THE NUTRITION SOCIETY 73 (OCE1) pp. E40-E40 CAMBRIDGE UNIV PRESS
Villela I, Heidenreich B, Cheema M, di Martino T, Samson LD, Meira LB (2011) Dissecting the mechanism of DNA damage induced photoreceptor cell death, TOXICOLOGY 290 (2-3) pp. 143-143
Meira LB, Cheo DL, Reis AM, Chaij N, Burns DK, te Riele H, Friedberg EC (2002) Mice defective in the mismatch repair gene Msh2 show increased predisposition to UVB radiation-induced skin cancer (vol 1, pg 929, 2002), DNA REPAIR 1 (12) PII S1568-7864(02)00200-8 pp. 1063-1063 ELSEVIER SCIENCE BV
Dong L, Meira LB, Hazra TK, Samson LD, Cao W (2006) Novel oxanine DNA glycosylase activities in mammalian systems., ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 47 (6) pp. 449-449 WILEY-LISS
Graham JM, Meira LB, Greenberg CR, Jaspers NGJ, Busch D, Coleman DM, Ziffer DW, Friedberg EC (1999) Original COFS syndrome Manitoba Aboriginal kindred has a mutation in the Cockayne syndrome group B (CSB) gene., AMERICAN JOURNAL OF HUMAN GENETICS 65 (4) pp. A299-A299 UNIV CHICAGO PRESS
Cheo DL, Ruven HJT, Meira LB, Hammer RE, Burns DK, Tappe NJ, vanZeeland AA, Mullenders LHF, Friedberg EC (1997) Characterization of defective nucleotide excision repair in XPC mutant mice, MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS 374 (1) pp. 1-9 ELSEVIER SCIENCE BV
Kobayashi K, Meira LB, Samson LD (2003) Transcriptional responses of Aag knockout mouse embryonic stem cells upon exposure to Me-Lex., TOXICOLOGICAL SCIENCES 72 pp. 256-256 OXFORD UNIV PRESS
Graham JM, Meira LB, Greenberg CR, Busch DB, Doughty ATB, Ziffer DW, Coleman DM, Savre-Train I, Friedberg EC (2000) Original COFS syndrome Manitoba Aboriginal kindred has a mutation in the Cockayne syndrome group B (CSB) gene, PEDIATRIC RESEARCH 47 (4) pp. 81A-81A INT PEDIATRIC RESEARCH FOUNDATION, INC
Longerich S, Meira L, Shah D, Samson LD, Storb U (2007) Alkyladenine DNA glycosylase (Aag) in somatic hypermutation and class switch recombination, DNA REPAIR 6 (12) pp. 1764-1773 ELSEVIER SCIENCE BV
Meira LB, Burgis NE, Samson LD (2005) Base excision repair, In: Back N, Cohen IR, Kritchevsky D, Lajtha A, Paoletti R, Nigg EA (eds.), Genome Instability in Cancer Development 570 pp. 125-173 SPRINGER
Lingaraju GM, Kartalou M, Meira LB, Samson LD (2008) Substrate specificity and sequence-dependent activity of the Saccharomyces cerevisiae 3-methyladenine DNA glycosylase (Mag), DNA REPAIR 7 (6) pp. 970-982 ELSEVIER SCIENCE BV
Meira LB, Cheo DL, Hammer RE, Burns DK, Reis A, Friedberg EC (1997) Genetic interaction between HAP1/REF-1 and p53, NATURE GENETICS 17 (2) pp. 145-145 NATURE PUBLISHING CO
Meira LB, Samson L (2003) Complex responses to damaging agents, DRUG METABOLISM REVIEWS 35 pp. 15-15 MARCEL DEKKER INC
Kisby GE, Fry RC, Lasarev MR, Bammler TK, Beyer RP, Churchwell M, Doerge DR, Meira LB, Palmer VS, Ramos-Crawford A-L, Ren X, Sullivan RC, Kavanagh TJ, Samson LD, Zarbl H, Spencer PS (2011) The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner, PLOS ONE 6 (6) ARTN e20911 PUBLIC LIBRARY SCIENCE
Klapacz J, Meira LB, Luchetti DG, Calvo JA, Bronson RT, Edelmann W, Samson LD (2009) O-6-methylguanine-induced cell death involves exonuclease 1 as well as DNA mismatch recognition in vivo, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 106 (2) pp. 576-581 NATL ACAD SCIENCES
Shah D, Marinov G, Meira L, Samson L (2006) Cellular responses to 3-methyladenine DNA lesions., ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 47 (6) pp. 467-467 WILEY-LISS
Lee CW, Rickman B, Meira LB, Samson L, Fox JG (2007) Base excision repair genes alkyl adenine DNA glycosylase (Aag) and O6-methylguanine DNA methyltransferase (Mgmt) suppresses Helicobacter pylori-associated inflammation and progression to cancer, GASTROENTEROLOGY 132 (4) pp. A319-A319 W B SAUNDERS CO-ELSEVIER INC
Beyer RP, Fry RC, Lasarev MR, McConnachie LA, Meira LB, Palmer VS, Powell CL, Ross PK, Bammler TK, Bradford BU, Cranson AB, Cunningham ML, Fannin RD, Higgins GM, Hurban P, Kayton RJ, Kerr KF, Kosyk O, Lobenhofer EK, Sieber SO, Vliet PA, Weis BK, Wolfinger R, Woods CG, Freedman JH, Linney E, Kaufmann WK, Kavanagh TJ, Paules RS, Rusyn I, Samson LD, Spencer PS, Suk W, Tennant RJ, Zarbl H (2007) Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses, TOXICOLOGICAL SCIENCES 99 (1) pp. 326-337 OXFORD UNIV PRESS
Ham AJL, Engelward BP, Koc H, Sangaiah R, Meira LB, Samson LD, Swenberg JA (2004) New immunoaffinity-LC-MS/MS methodology reveals that Aag null mice are deficient in their ability to clear 1,N-6-etheno-deoxyadenosine DNA lesions from lung and liver in vivo, DNA REPAIR 3 (3) pp. 257-265 ELSEVIER SCIENCE BV
Cheo DL, Burns DK, Meira LB, Houle JF, Friedberg EC (1999) Mutational inactivation of the xeroderma pigmentosum group C gene confers predisposition to 2-acetylaminofluorene-induced liver and lung cancer and to spontaneous testicular cancer in Trp53(-/-) mice, CANCER RESEARCH 59 (4) pp. 771-775 AMER ASSOC CANCER RESEARCH
Klapacz J, Meira LB, Edelmann W, Samson LD (2004) Investigating the role of exonuclease I in the O-6-methylguanine-induced apoptosis, ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 44 (3) pp. 210-210 WILEY-LISS
Ringvoll J, Moen MN, Nordstrand LM, Meira LB, Pang B, Bekkelund A, Dedon PC, Bjelland S, Samson LD, Falnes PO, Klungland A (2008) AlkB homologue 2-mediated repair of ethenoadenine lesions in mammalian DNA, CANCER RESEARCH 68 (11) pp. 4142-4149 AMER ASSOC CANCER RESEARCH
Friedberg EC, Meira LB, Cheo DL (1997) Database of mouse strains carrying targeted mutations in genes affecting cellular responses to DNA damage, MUTATION RESEARCH-DNA REPAIR 383 (2) pp. 183-188 ELSEVIER SCIENCE BV
Reis AM, Cheo DL, Meira LB, Greenblatt MS, Bond JP, Nahari D, Friedberg EC (2000) Genotype-specific Trp53 mutational analysis in ultraviolet B radiation-induced skin cancers in Xpc and Xpc Trp53 mutant mice, CANCER RESEARCH 60 (6) pp. 1571-1579 AMER ASSOC CANCER RESEARCH
Shah NR, Meira L, Elliott RM, Howlett PJ, Brown AJ, Williams M, West NE, Hoole S, Mahmoudi M (2015) DNA repair activity determines atherosclerotic plaque stability in patients with stable coronary artery disease, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 66 (15) pp. B124-B124 ELSEVIER SCIENCE INC
Graham JM, Meira LB, Greenberg CR, Busch D, Friedberg EC (2000) Original COFS syndrome kindred from Manitoba has a mutation in the cockayne syndrome group B (CSB) gene., JOURNAL OF INVESTIGATIVE MEDICINE 48 (1) pp. 48A-48A LIPPINCOTT WILLIAMS & WILKINS
Calvo J, Meira L, Lee C-Y, Moroski-Erkul C, Abolhassani N, Taghizadeh K, Muthupalani S, Nordstrand L, Klungland A, Samson L (2012) DNA Repair Is Indispensable for Survival after Acute Inflammation in Mice, ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 53 pp. S14-S14 WILEY-BLACKWELL
Meira LB, Bugni JM, Green SL, Lee C-W, Pang B, Borenshtein D, Rickman BH, Rogers AB, Moroski-Erkul CA, McFaline JL, Schauer DB, Dedon PC, Fox JG, Samson LD (2008) DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice, JOURNAL OF CLINICAL INVESTIGATION 118 (7) pp. 2516-2525 AMER SOC CLINICAL INVESTIGATION INC
Meira LB, Cheo DL, Reis AM, Claij N, Burns DK, Riele HT, Friedberg EC (2002) Mice defective in the mismatch repair gene Msh2 show increased predisposition to UVB radiation-induced skin cancer, DNA REPAIR 1 (11) PII S1568-7864(02)00143-X pp. 929-934 ELSEVIER SCIENCE BV
Calvo JA, Moroski-Erkul CA, Lake A, Eichinger LW, Shah D, Jhun I, Limsirichai P, Bronson RT, Christiani DC, Meira LB, Samson LD (2013) Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1, PLoS Genetics 9 (4)
Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic ²-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag-/- mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage. © 2013 Calvo et al.
Meira LB, Reis AMC, Cheo DL, Nahari D, Burns DK, Friedberg EC (2001) Cancer predisposition in mutant mice defective in multiple genetic pathways: uncovering important genetic interactions, MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS 477 (1-2) pp. 51-58 ELSEVIER SCIENCE BV
Bordin DL, Lima M, Lenz G, Saffi J, Meira LB, Mésange P, Soares DG, Larsen AK, Escargueil AE, Henriques JAP (2013) DNA alkylation damage and autophagy induction, Mutation Research - Reviews in Mutation Research 753 (2) pp. 91-99
Many alkylating agents are used as chemotherapeutic drugs and have a long history of clinical application. These agents inflict a wide range of DNA damage resulting in a complex cellular response. After DNA damage, cells trigger a series of signaling cascades promoting cellular survival and cell cycle blockage which enables time for DNA repair to occur. More recently, induction of autophagy has been observed in cancer cells after treatment with different DNA-targeted anticancer drugs, including alkylating agents. Several studies have demonstrated that induction of autophagy after DNA damage delays apoptotic cell death and may therefore lead to chemoresistance, which is the limiting factor for successful chemotherapy. On the other hand, depending on the extent of damage and the cellular context, the induction of autophagy may also contribute to cell death. Given these conflicting results, many studies have been conducted to better define the role of autophagy in cancer cells in response to chemotherapy. In this review, we describe the main alkylating agents used in clinical oncology as well as the cellular response they evoke with emphasis on autophagy. © 2013 Elsevier B.V.
Barazzuol L, Jena R, Burnet NG, Meira LB, Jeynes JC, Kirkby KJ, Kirkby NF (2013) Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma., Radiat Oncol 8
The cytotoxicity of radiotherapy and chemotherapy can be enhanced by modulating DNA repair. PARP is a family of enzymes required for an efficient base-excision repair of DNA single-strand breaks and inhibition of PARP can prevent the repair of these lesions. The current study investigates the trimodal combination of ABT-888, a potent inhibitor of PARP1-2, ionizing radiation and temozolomide(TMZ)-based chemotherapy in glioblastoma (GBM) cells.
Meira LB, Devaraj S, Kisby GE, Burns DK, Daniel RL, Hammer RE, Grundy S, Jialal I, Friedberg EC (2001) Heterozygosity for the mouse Apex gene results in phenotypes associated with oxidative stress, CANCER RESEARCH 61 (14) pp. 5552-5557 AMER ASSOC CANCER RESEARCH
Meira LB, Graham JM, Greenberg CR, Busch DB, Doughty ATB, Ziffer DW, Coleman DM, Savre-Train I, Friedberg EC (2000) Manitoba aboriginal kindred with original cerebro-oculo-facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene, AMERICAN JOURNAL OF HUMAN GENETICS 66 (4) pp. 1221-1228 UNIV CHICAGO PRESS
Friedberg EC, Bond JP, Burns DK, Cheo DL, Greenblatt MS, Meira LB, Nahari D, Reis AM (2000) Defective nucleotide excision repair in Xpc mutant mice and its association with cancer predisposition, MUTATION RESEARCH-DNA REPAIR 459 (2) pp. 99-108 ELSEVIER SCIENCE BV
Meira LB, Calvo JA, Shah D, Klapacz J, Moroski-Erkul CA, Bronson RT, Samson LD (2014) Repair of endogenous DNA base lesions modulate lifespan in mice., DNA Repair (Amst) 21 pp. 78-86
The accumulation of DNA damage is thought to contribute to the physiological decay associated with the aging process. Here, we report the results of a large-scale study examining longevity in various mouse models defective in the repair of DNA alkylation damage, or defective in the DNA damage response. We find that the repair of spontaneous DNA damage by alkyladenine DNA glycosylase (Aag/Mpg)-initiated base excision repair and O(6)-methylguanine DNA methyltransferase (Mgmt)-mediated direct reversal contributes to maximum life span in the laboratory mouse. We also uncovered important genetic interactions between Aag, which excises a wide variety of damaged DNA bases, and the DNA damage sensor and signaling protein, Atm. We show that Atm plays a role in mediating survival in the face of both spontaneous and induced DNA damage, and that Aag deficiency not only promotes overall survival, but also alters the tumor spectrum in Atm(-/-) mice. Further, the reversal of spontaneous alkylation damage by Mgmt interacts with the DNA mismatch repair pathway to modulate survival and tumor spectrum. Since these aging studies were performed without treatment with DNA damaging agents, our results indicate that the DNA damage that is generated endogenously accumulates with age, and that DNA alkylation repair proteins play a role in influencing longevity.
Bugni JM, Meira LB, Samson LD (2009) Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins, ONCOGENE 28 (5) pp. 734-741 NATURE PUBLISHING GROUP
Alasmael N, Mohan R, Meira LB, Swales KE, Plant NJ (2015) Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential, CANCER LETTERS 370 (2) pp. 250-259 ELSEVIER IRELAND LTD
Meira LB, Pease K, Kerrison F, Dong M, Fry R, Dedon P, Samson LD (2004) Defective repair of alkylation DNA damage in mice, ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 44 (3) pp. 215-215 WILEY-LISS
Raffoul JJ, Cabelof DC, Nakamura J, Meira LB, Friedberg EC, Heydari AR (2004) Apurinic/apyrimidinic endonuclease (APE/REF-1) haploinsufficient mice display tissue-specific differences in DNA polymerase beta-dependent base excision repair, JOURNAL OF BIOLOGICAL CHEMISTRY 279 (18) pp. 18425-18433 AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Cheo DL, Meira LB, Hammer RE, Burns DK, Doughty ATB, Friedberg EC (1996) Synergistic interactions between XPC and p53 mutations in double-mutant mice: Neural tube abnormalities and accelerated UV radiation-induced skin cancer, CURRENT BIOLOGY 6 (12) pp. 1691-1694 CURRENT BIOLOGY LTD
Meira LB, Moroski-Erkul CA, Green SL, Calvo JA, Bronson RT, Shah D, Samson LD (2009) Aag-initiated base excision repair drives alkylation-induced retinal degeneration in mice., Proc Natl Acad Sci U S A 106 (3) pp. 888-893
Vision loss affects >3 million Americans and many more people worldwide. Although predisposing genes have been identified their link to known environmental factors is unclear. In wild-type animals DNA alkylating agents induce photoreceptor apoptosis and severe retinal degeneration. Alkylation-induced retinal degeneration is totally suppressed in the absence of the DNA repair protein alkyladenine DNA glycosylase (Aag) in both differentiating and postmitotic retinas. Moreover, transgenic expression of Aag activity restores the alkylation sensitivity of photoreceptors in Aag null animals. Aag heterozygotes display an intermediate level of retinal degeneration, demonstrating haploinsufficiency and underscoring that Aag expression confers a dominant retinal degeneration phenotype.
Dong L, Glass RA, Meira LB, Samson LD, Cao W (2007) Novel xanthine DNA glycosylase (XDG) activities in mammalian and yeast systems., ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 48 (7) pp. 569-569 WILEY-LISS
Unnikrishnan A, Raffoul JJ, Patel HV, Prychitko TM, Anyangwe N, Meira LB, Friedberg EC, Cabelof DC, Heydari AR (2009) Oxidative stress alters base excision repair pathway and increases apoptotic response in apurinic/apyrimidinic endonuclease 1/redox factor-1 haploinsufficient mice, FREE RADICAL BIOLOGY AND MEDICINE 46 (11) pp. 1488-1499 ELSEVIER SCIENCE INC
Maor-Shoshani A, Meira LB, Yang X, Samson LD (2008) 3-methyladenine DNA glycosylase ill important for cellular resistance to psoralen interstrand cross-links, DNA REPAIR 7 (8) pp. 1399-1406 ELSEVIER SCIENCE BV
Brignull LM, Czimmerer Z, Saidi H, Daniel B, Villela I, Bartlett NW, Johnston SL, Meira LB, Nagy L, Nohturfft A (2013) Reprogramming of lysosomal gene expression by interleukin-4 and Stat6, BMC Genomics 14 (1)
Background: Lysosomes play important roles in multiple aspects of physiology, but the problem of how the transcription of lysosomal genes is coordinated remains incompletely understood. The goal of this study was to illuminate the physiological contexts in which lysosomal genes are coordinately regulated and to identify transcription factors involved in this control.Results: As transcription factors and their target genes are often co-regulated, we performed meta-analyses of array-based expression data to identify regulators whose mRNA profiles are highly correlated with those of a core set of lysosomal genes. Among the ~50 transcription factors that rank highest by this measure, 65% are involved in differentiation or development, and 22% have been implicated in interferon signaling. The most strongly correlated candidate was Stat6, a factor commonly activated by interleukin-4 (IL-4) or IL-13. Publicly available chromatin immunoprecipitation (ChIP) data from alternatively activated mouse macrophages show that lysosomal genes are overrepresented among Stat6-bound targets. Quantification of RNA from wild-type and Stat6-deficient cells indicates that Stat6 promotes the expression of over 100 lysosomal genes, including hydrolases, subunits of the vacuolar H+ ATPase and trafficking factors. While IL-4 inhibits and activates different sets of lysosomal genes, Stat6 mediates only the activating effects of IL-4, by promoting increased expression and by neutralizing undefined inhibitory signals induced by IL-4.Conclusions: The current data establish Stat6 as a broadly acting regulator of lysosomal gene expression in mouse macrophages. Other regulators whose expression correlates with lysosomal genes suggest that lysosome function is frequently re-programmed during differentiation, development and interferon signaling. © 2013 Brignull et al.; licensee BioMed Central Ltd.
Hitchcock TM, Dong L, Connor EE, Meira LB, Samson LD, Wyatt MD, Cao WG (2004) Oxanine DNA glycosylase activity from mammalian alkyladenine glycosylase, JOURNAL OF BIOLOGICAL CHEMISTRY 279 (37) pp. 38177-38183 AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Dong L, Meira LB, Hazra TK, Samson LD, Cao W (2008) Oxanine DNA glycosylase activities in mammalian systems, DNA REPAIR 7 (1) pp. 128-134 ELSEVIER SCIENCE BV
Cheo DL, Meira LB, Burns DK, Reis AM, Issac T, Friedberg EC (2000) Ultraviolet B radiation-induced skin cancer in mice defective in the Xpc, Trp53, and Apex (HAP1) genes: Genotype-specific effects on cancer predisposition and pathology of tumors, CANCER RESEARCH 60 (6) pp. 1580-1584 AMER ASSOC CANCER RESEARCH
Friedberg EC, Meira LB, Cheo DL (1998) Database of mouse strains carrying targeted mutations in genes affecting cellular responses to DNA damage. Version 2, MUTATION RESEARCH-DNA REPAIR 407 (3) pp. 217-226 ELSEVIER SCIENCE BV
Bordin DL, Lima M, Lenz G, Henriques JAP, Saffi J, Meira LB, Mésange P, Soares DG, Larsen AK, Escargueil AE (2013) DNA alkylation damage and autophagy induction, Mutation Research - Reviews in Mutation Research
Many alkylating agents are used as chemotherapeutic drugs and have a long history of clinical application. These agents inflict a wide range of DNA damage resulting in a complex cellular response. After DNA damage, cells trigger a series of signaling cascades promoting cellular survival and cell cycle blockage which enables time for DNA repair to occur. More recently, induction of autophagy has been observed in cancer cells after treatment with different DNA-targeted anticancer drugs, including alkylating agents. Several studies have demonstrated that induction of autophagy after DNA damage delays apoptotic cell death and may therefore lead to chemoresistance, which is the limiting factor for successful chemotherapy. On the other hand, depending on the extent of damage and the cellular context, the induction of autophagy may also contribute to cell death. Given these conflicting results, many studies have been conducted to better define the role of autophagy in cancer cells in response to chemotherapy. In this review, we describe the main alkylating agents used in clinical oncology as well as the cellular response they evoke with emphasis on autophagy. © 2013 Elsevier B.V. All rights reserved.
Alasmael N, Meira LB, Swales K, Plant N (2013) FXR is implicated in matrix metalloproteinases regulation, tumor invasion and metastasis in breast cancer, CANCER RESEARCH 73 (8) AMER ASSOC CANCER RESEARCH
Totti Stella, Vernardis SI, Meira Lisiane, Pérez-Mancera PA, Costello E, Greenhalf W, Palmer D, Neoptolemos J, Mantalaris A, Velliou Eirini (2017) Designing a bio-inspired bio-mimetic in vitro system for the optimisation of ex vivo studies of pancreatic cancer, Drug Discovery Today 22 (4) pp. 690-701 Elsevier
Pancreatic cancer is one of the most aggressive and lethal human malignancies. Drug therapies and radiotherapy are used for treatment as adjuvants to surgery, but outcomes remain disappointing. Advances in tissue engineering point that three-dimensional cultures can reflect the in vivo tumour micro-environment and can guarantee a physiological distribution of oxygen, nutrients and drugs, therefore, being promising low cost tools for therapy development. In this work we review crucial elements, i.e., structural and environmental, that should be considered for an accurate design of an ex vivo platform for studies of pancreatic cancer. Furthermore, we propose environmental stress response biomarkers as platform readouts for the efficient control and further prediction of the pancreatic cancer response to the environmental and treatment input.
Leguisamo N, Gloria H, Kalil A, Martins T, Azambuja D, Meira LB, Saffi J (2017) Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy, Oncotarget pp. 1-16 Impact Journals
Colorectal cancer (CRC) is prevalent worldwide, and treatment often involves surgery and genotoxic chemotherapy. DNA repair mechanisms, such as base excision repair (BER) and mismatch repair (MMR), may not only influence tumour characteristics and prognosis but also dictate chemotherapy response. Defective MMR contributes to chemoresistance in colorectal cancer. Moreover, BER affects cellular survival by repairing genotoxic base damage in a process that itself can disrupt metabolism. In this study, we characterized BER and MMR gene expression in colorectal tumours and the association between this repair profile with patients? clinical and pathological features. In addition, we exploited the possible mechanisms underlying the association between altered DNA repair, metabolism and response to chemotherapy. Seventy pairs of sporadic colorectal tumour samples and adjacent non-tumour mucosal specimens were assessed for BER and MMR gene and protein expression and their association with pathological and clinical features. MMR-deficient colon cancer cells (HCT116) transiently overexpressing MPG or XRCC1 were treated with 5-FU or TMZ and evaluated for viability and metabolic intermediate levels. Increase in BER gene and protein expression is associated with more aggressive tumour features and poor pathological outcomes in CRC. However, tumours with reduced MMR gene expression also displayed low MPG, OGG1 and PARP1 expression. Imbalancing BER by overexpression of MPG, but not XRCC1, sensitises MMR-deficient colon cancer cells to 5-FU and TMZ and leads to ATP depletion and lactate accumulation. MPG overexpression alters DNA repair and metabolism and is a potential strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.
Healing Eleanor, Meira Lisiane, Aston Philip, Tindall M.J., Elliott Ruan (2016) Measurement of DNA repair activity in hepatocytes exposed to fatty acids, Proceedings of the Nutrition Society Volume 75, Issue OCE3 (Summer Meeting, 11?14 July 2016, New technology in nutrition research and practice) 75 (OCE3)
DNA repair capacity varies greatly between individuals, and evidence has begun to link this variation to cancer risk, obesity and related chronic diseases. There is also emerging evidence that dietary components can affect DNA repair, but research to date has been restricted by methods for measuring DNA repair. This study made use of newly developed microplate-based assays for the direct determination of DNA repair enzyme activities. Lipid loading of the HepG2 human hepatocellular carcinoma cell line was employed as a model to test the hypothesis that hepatic steatosis affects DNA repair activity via induction of oxidative stress.
It is estimated that 10,000 lesions arise in the genome of a cell every day. Cells have therefore also evolved ways to protect the integrity of their genomes using direct DNA repair enzymes and multi-step pathways including base excision repair and nucleotide excision repair. Alkylating agents are reactive chemicals that transfer alkyl groups to biological molecules, including DNA. The base excision repair pathway mainly repairs non-bulky lesions produced by alkylation, oxidation or deamination of bases. This pathway is initiated by alkyladenine DNA glycosylase (Aag).
Antioxidants neutralise free radicals including reactive oxygen specied (ROS), and have been widely reported to protect against disease. However, some studies have also reported that anti-oxidants may instead make disease progression worse. This thesis aims at evaluating the role of antioxidants in the cellular response to the alkylating agent, methylmethane sulfonate.
WT and Aag-deficient mouse embryonic fibroblasts (MEFs) were pre-treated with the antioxidant N-acetylcysteine (NAC) and exposed to MMS. NAC increased MMS-induced cell death in both Aag-deficient and wild-type (WT) MEFs. These were further confirmed with embryonic stem cells (ESc) being also sensitized to MMS-induced cell death by the anti-oxidant 2-mercaptoethanol (2-ME); and with 661W photoreceptor cells being sensitised to MMS-induced cell death by a commercial antioxidant mixture and NAC.
MEFs exhibited ROS generation when exposed to MMS, which was abrogated with NAC. The mitochondrial superoxide probe MitoSox proves that the MMS-induced ROS generation did not originate from the mitochondria. The NADPH oxidase inhibitor Diphenyleneiodonium (DPI) abrogated MMS-induced ROS generation and also sensitised cells to MMS in a similar fashion to NAC. Collectively, we conclude that cells generate ROS as a response to MMS treatment, and that this ROS generation is essential for cell survival.
We also show by using different glucose concentrations, ATP levels appear to be irrelevant to MMS-induced cell death, and that higher basal NAD levels correlates with higher amount of MMS-induced cell death.
Selenium (Se) is associated with insulin resistance and may affect endothelial function thereby increasing the risk of type 2 diabetes and associated cardiovascular disease (CVD). However, the molecular mechanisms involved are not clear. The endoplasmic-reticulum (ER) stress response is a mechanism involved in apoptosis induced by high Se in some cancer cells and, also in the pathogenesis of insulin resistance and endothelial dysfunction (ED). Thus, we hypothesised that high Se status causes ED through ER stress response. Endothelial cells (HUVECs) and EA.hy926 cell lines were treated with selenite (0.5-10 µM) for 24 hours in the presence or absence of the ER chemical chaperone, 4-phenylbutryic acid (PBA). ER stress markers were investigated using qPCR and western-blot technique. Endothelial function was assessed by the Griess assay, flow cytometry, Matrigel® and colourimetric assays. Data were expressed as S.E.M (p High Se concentration (5-10 µM) compared to physiological concentration (0.5?2.0 µM) enhanced mRNA expression of ER-stress markers:- activating transcription factor-4 (ATF4), CAAA/enhanced-binding homologous protein (CHOP) and X-binding box-1 (XBP-1). In addition, high selenite concentration reduced nitric oxide production and angiogenic capacity in endothelial cells. Moreover, high selenite treatment significantly (p Interestingly, PBA completely reversed all the effects of high selenite on endothelial function, indicating the involvement of the ER-stress response. High Se treatment caused endothelial dysfunction through the activation of the ER-stress response. This thesis additionally warns the public to be aware of the risks of the use of Se supplements as a prophylactic agent against oxidative-stress disease.
The genome is a very dynamic store of genetic information and constantly threatened by endogenous and exogenous damaging agents. To maintain fidelity of the information stored, several robust and overlapping repair pathways, such as the Base Excision Repair (BER) pathway, have evolved. The main BER glycosylase responsible for repairing alkylation DNA damage is the alkyladenine DNA glycosylase (AAG). Repair initiated by AAG can lead to accumulation of cytotoxic intermediates. Here, we report the involvement of AAG in the elicitation of the unfolded protein response (UPR), a mechanism triggered to restore proteostasis in the cell whose dysfunction is implicated in diseases like diabetes, Alzheimer?s disease and cancer. Firstly, we determined that not only human ARPE-19 cells were capable of eliciting the UPR, but that an alkylating agent, methyl methanesulfonate (MMS), also triggers the response, and that in the absence of AAG the response is greatly diminished. Our luciferase reporter assay indicates that the response is activated on multiple branches (IRE1 and ATF6) on both AAG-proficient and deficient cells. Although no transcriptional induction of UPR markers was detected by RT-qPCR at 6 hours post MMS treatment, preliminary western-blot data at 6 and 24h, show activation of key UPR markers (p-eIF2±, BiP and XBP-1) upon MMS treatment in wild-type cells and little or no activation on AAG -/-. To investigate the impact of AAG modulation on the cellular proteome we also conducted a proteomic analysis, identifying 5480 protein groups in wild-type ARPE-19, 5377 in the AAG -/- A2C2 and 5264 in AAG -/- B6C3. After a high-stringency analysis, we identified 13 proteins present only in wild-type cells, indicating promising targets for further investigation into the role of AAG in the UPR. We also identified 44 overrepresented GO-slim terms across all cell lines and 23 overrepresented pathways, mostly related to cellular metabolism processes. Whereas more experiments are required to characterize the nature of AAG?s contribution to the UPR, we demonstrate the existence of crosstalk between the DNA repair response and the ER stress response pathways, that is potentially relevant in a clinical setting.
Glioblastoma is an aggressive brain cancer with a median survival rate of 14.6 months post diagnosis. Treatments for glioblastoma include surgery, radiotherapy, and chemotherapy with the alkylating agent temozolomide (TMZ). In 50% of patients, TMZ treatment is ineffective due to the reparative action of the protein O6- MeG DNA methyltransferase (MGMT). The base excision repair (BER) pathway repairs the most common lesions caused by TMZ.

This work reports the characterization of several glioblastoma cell lines in terms of their repair status and sensitivity to traditional therapy of X-ray irradiation and TMZ. We find that the expression of BER proteins differed between cell lines, with alkyladenine-DNA-glycosylase (AAG) showing the greatest variation in expression. Sensitivity to TMZ and X-rays was MGMT dependent. Moreover, our results suggest that cell lines expressing higher AAG levels display increased sensitivity to X-rays and TMZ combination treatment in an MGMT independent fashion.

Pharmacological inhibition of BER enzymes AP-endonuclease (APE) and polymerase b (PolB) was examined, intending to enhance sensitivity of the glioblastoma cell lines to TMZ and X-ray or proton treatment. Methoxyamine (MX), an inhibitor of AP-endonuclease (APE) activity, leads to a modest increase in TMZ sensitivity. The combination of X-rays, MX and TMZ sensitised MGMT-negative cell lines, this was not seen in proton radiation. PolB inhibition greatly increased TMZ toxicity in conjunction with radiation in glioblastoma cell lines.

Proton irradiation systems were analysed and developed within this work, leading to a high-throughput broadbeam irradiation system. These methodologies lead to differences being detected in response to proton irradiation depending on the method used. This might in future, lead to further understanding of low-dose hypersensitivity.

In conclusion, the modulation of BER can enhance glioblastoma sensitivity to current treatment modalities, however, this is in an MGMT dependent fashion. These studies could provide insight for current clinical trials.

Base excision repair (BER) is a pathway that repairs DNA damage inflicted by oxidative stress, certain alkylating agents, and spontaneous hydrolysis. Assays to measure the BER pathway are usually limited by being low-throughput, time consuming, and unable to measure each step of the pathway in addition to complete repair. The aim of the present work was to develop an assay format to overcome these limitations, and use this to develop a mathematical
model to examine differences between cell types on flux through the pathway. A novel assay format was developed and optimised to measure uracil DNA glycosylase, AP endonuclease, DNA polymerase ², DNA ligase, AP site repair and complete base repair. Data was generated for each enzyme activity in HepG2, Caco-2, and peripheral blood mononuclear cells (PBMCs), and the effects on the pathway were predicted using a mathematical model. In addition, the assay was used to examine variability in enzyme activity between the two cell lines, correlations between enzyme activities in primary human cells, and the effects of caloric restriction on BER in a human weight loss intervention trial. The model revealed marked differences in the response to aberrant uracil between the two immortalised cell lines and the PBMCs, with PBMC nuclear extract in general excising the base more slowly and causing a smaller and slower accumulation of harmful intermediates, such as abasic sites and single strand breaks, compared to the immortalised cell lines. The model underestimated complete repair when compared to the biological data for all cell types, potentially due to cooperativity between BER enzymes not captured when repair steps were measured individually under experimental conditions. There were also significant correlations found between enzyme activities in PBMC extracts from different individuals, and a significant predictive effect of weight loss method on polymerase ² activity in the caloric restriction trial. In conclusion, the research described here uncovered novel information regarding the effects of weight loss on DNA repair, and correlations between BER enzyme activities in healthy volunteers. This is also the first work to compare BER profiles of different cell types using biological data and mathematical modelling.
Healing Eleanor, Charlier Clara. F, Meira Lisie, Elliott Ruan (2019) A panel of colorimetric assays to measure enzymatic activity in the base excision DNA repair pathway, Nucleic Acids Research 47 (11) e61 Oxford University Press
DNA repair is essential for the maintenance of genomic integrity, and evidence suggest that interindividual variation in DNA repair efficiency maycontribute to disease risk. However, robust assays suitable for quantitative determination of DNA repair capacity in large cohort and clinical trials are needed to evaluate these apparent associations fully. We describe here a set of microplate-based oligonucleotide assays for high-throughput, non-radioactiveand quantitative determination of repair enzyme activity at individual steps and over multiple steps of
the DNA base excision repair pathway. The assays are highly sensitive: using HepG2 nuclear extract, enzyme activities were quantifiable at concentrationsof 0.0002 to 0.181 g per reaction, depending on the enzyme being measured. Assay coefficients of variation are comparable with other microplate-based assays. The assay format requires no specialist equipment and has the potential to be extended for analysis of a wide range of DNA repair enzyme activities. As such, these assays hold considerable promise for gaining new mechanistic insights into how DNA repair is related to individual genetics, disease status or progression and other environmental factors and investigating whether DNA repair activities can be used a biomarker of disease risk.
Despite therapeutic and interventional technological advances, the global burden of cardiovascular disease is increasing. Accumulated deoxyribonucleic acid (DNA) damage and subsequent repair pathways are now increasingly recognised as a causal factor in the initiation and progression of atherosclerosis. These molecular alterations have been shown to occur within affected vasculature, plaque microenvironment as well as in circulating cells. The DNA damage response (DDR) pathway is reliant on post-translational modification of sensing proteins which activate a signalling cascade to repair, if possible, DNA damaged sites in response to various environmental and physiological insults.
Most studies to-date have focussed on animal models and cells cultured directly from atherosclerotic plaque to ascertain if altered DDR and DNA repair exist and indeed contribute to the atherosclerotic process. By using peripheral whole blood as the base for down-stream analyses, an accessible method of determining if altered expression of genes involved in DDR and enzymes involved in DNA repair could be exploited.

DNA ligase is crucial in single (ssDNA) and double-stranded DNA break repair (DSBR) by facilitating the joining of DNA strands by catalysing phosphodiester bond formation. It was therefore chosen as a marker of DNA repair being a key enzyme involved in base excision repair (BER) and DSBR.

This study examined the differential expression of 22 genes pertinent in the DNA damage and response pathway (DDR), in addition to DNA ligase activity, between patients with stable, unstable coronary atherosclerosis (both undergoing percutaneous coronary intervention for obstructive coronary disease) and healthy controls. In addition, correlations were performed between atherosclerotic plaque features and both DNA ligase activity and the genes of interest. To accurately analyse plaque morphology, frequency domain optical coherence tomography (FD-OCT) was used which allowed high resolution delineation of fibrous tissue, lipid accumulation, calcific deposition and fibrous cap thickness, all key features in plaque vulnerability and therefore of clinical significance.

Peripheral blood mononuclear cells (PBMC) were isolated and DNA repair activity was measured from derived nuclear extracts, using a novel microplate assay examining mean
apparent DNA ligase activity. A custom microarray for the 22 genes of interest was used to perform quantitative reverse transcription polymerase chain reaction for differential gene expression between all 3 cohorts of patients recruited.

Data from this study demonstrated differences in DNA ligase activity and expression of genes involved in the DDR in patients with coronary atherosclerosis. DNA ligase activity correlated with the arc of lipid and cap thickness in both stable and unstable coronary patients. Differential DDR gene expression also correlated with fibrous cap thickness, predominantly in the unstable coronary group. This suggests that such alterations may contribute to the development and progression of the atherosclerotic lipid rich necrotic core as well as protective fibrous cap thickness.

Although significant correlations were found between DNA ligase, genes of interest and plaque features, this study demonstrates an association but does not provide a direct mechanism by which alterations in DDR contribute to atherogenesis.

Further studies are required to address differential expression across a broader spectrum of genes involved in DDR in coronary artery disease.

Shah Nikunj, Meira Lisiane B., Elliott Ruan M., Hoole Stephen P., West Nick E., Brown Adam J., Bennett Martin R., Garcia-Garcia Hector M., Kuku Kayode O., Dan Kazuhiro, Kolm Paul, Mariathas Mark, Curzen Nick, Mahmoudi Michael (2019) DNA damage and repair in patients with coronary artery disease: Correlation with plaque morphology using optical coherence tomography (DECODE study), Cardiovascular Revascularization Medicine 20 (9) pp. 812-818 Elsevier


The aim of this study was to examine DNA ligase activity and expression of DNA damage response pathway (DDR) genes in patients with stable angina (SA) and non-ST elevation myocardial infarction (NSTEMI) and determine whether they correlate with plaque morphology.


Patients with coronary artery disease (CAD) have evidence of deoxyribonucleic acid (DNA) damage in peripheral blood mononuclear cells (PBMCs). It is unclear whether this represents excess damage or defective DNA repair activity.


DNA ligase activity and the expression of 22 DDR genes were measured in PBMCs of patients (both SA (n/=/47) and NSTEMI (n/=/42)) and in age and gender-matched controls (n/=/35). Target lesion anatomical assessment was undertaken with frequency domain optical coherent tomography.


DNA ligase activity was different across the three groups of patients (control/=/119/±/53, NSTEMI/=/115.6/±/85.1, SA/=/81/±/55.7/units/g of nuclear protein; ANOVA p/=/0.023). Pair wise comparison demonstrated that this significance is due to differences between the control and SA patients (p/=/0.046). Genes involved in double strand break repair and nucleotide excision repair pathways were differentially expressed in patients with SA and NSTEMI. In SA patients, fibrocalcific plaques were strongly associated with GTSE1, DDB1, MLH3 and ERCC1 expression. By contrast, in NSTEMI patients the strongest association was observed between fibrous plaques and ATM and XPA expression.


PBMCs from patients with CAD exhibit differences in DNA ligase activity and expression of DDR genes. Expression levels of certain DDR genes are strongly associated with plaque morphology and may play a role in plaque development and progression.

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