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Consequences of repair deficiencies in damaged genome

Grant number: 14/15982-6
Support type:Research Projects - Thematic Grants
Duration: November 01, 2014 - October 31, 2019
Field of knowledge:Biological Sciences - Genetics - Mutagenesis
Principal researcher:Carlos Frederico Martins Menck
Grantee:Carlos Frederico Martins Menck
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Maria Isabel Alves de Souza Waddington Achatz ; Rodrigo da Silva Galhardo ; Veridiana Munford
Associated grant(s):15/50080-6 - Impact of the circadian clock on the DNA repair capacity and drug sensitivity of normal and cancer cells: towards chronopersonalized chemotherapy, AP.R SPRINT
15/00296-2 - Multi-User Equipment approved in the grant 2014/15982-6: benchwork flow cytometer, AP.EMU
Associated scholarship(s):18/10061-0 - Role of translesion synthesis in cisplatin and temozolomide resistance in Glioma cells, BP.DR
18/02853-4 - Characterization of Transcription Coupled Repair deficient cells in response to oxidative stress, BP.IC
18/06619-6 - Application of bioinformatics in human mutagenesis studies using human exome data, BP.TT
+ associated scholarships 17/24217-0 - Mechanisms of tumor resistance to cisplatin: DNA lesions processing and circadian cycle effect, BP.DD
18/05216-5 - Genotypic characterization of Brazilian xeroderma pigmentosum patients and search for founder effects, BP.PD
17/24418-5 - Analisys of basal mutagenesis and UVA induced damages on Xeroderma Pigmentosum Variant patient cells, BP.DD
17/18781-0 - The role of XPG endonuclease in nuclear RNA transcription and in the maintenance of mitochondrial genome, BP.DD
17/10502-4 - Relevance of oxidative stress in induced pluripotent cells and neural progenitors derived from Cockayne Syndrome patients, BP.DD
17/12338-7 - Effects of ATR inhibition in the sensitivity of HPV +/- tumor cells to cisplatin, BP.IC
17/05680-0 - Mechanisms of translesion synthesis in human cells, BP.DD
16/05569-0 - Developing of isogenic cell lineages with different aleles XPG through transduction with lentiviral vectors, BP.IC
15/25016-2 - Exploring the role of NRF2 and circadian cycle as mediators of tumor resistance to chemotherapy, BP.PD
15/20368-8 - The effect of specific photoremoval of UVB induced lesions in DNA repair deficient mice, BP.DD
15/15184-5 - Characterization of lung cancer cell lines for resistance to cisplatin, BP.IC
15/00198-0 - Replication of ultraviolet-damaged DNA in human cells: different mechanisms for different lesions?, BP.IC
14/04157-4 - Modulating the activity of DNA repair proteins to improve chemotherapy effects, BP.PD - associated scholarships

Abstract

The genetic material is under constant assault from the environment or by-products of cell metabolism, inducing damage in the DNA molecule. Cells exhibit several responses, which protect from these lesions, including removal by DNA repair mechanisms, or DNA damage tolerance, where the genetic material can be replicated or transcribed, despite the damage. Our group has been working on scientific questions that try to understand how these mechanisms and cellular responses operate maintaining genomic stability, as well as what are the consequences of unrepaired DNA damage for cells and organisms. The importance of these systems for cell function is attested by the high degree of evolutionary conservation and, in humans, dramatically illustrated by genetic syndromes related to defects in DNA repair mechanisms or impairment of responses to DNA injuries. These defects result in clinical phenotypes such as high frequency of carcinogenesis, development problems, neurodegeneration and premature aging. Thus, an important part of this project focus studies in human cells, especially those derived from patients with deficiencies in DNA repair mechanisms, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), trichothiodystrophy (TTD), and other syndromes identified more recently. In one of the subprojects, we propose to investigate the damaging effects of the UV components of sunlight. The mechanism of DNA damage formation by UVA irradiation, for example, is not fully understood, nor the cellular responses to these lesions, especially in relation to death or mutagenesis. Given the importance of oxidative processes in the generation of cellular endogenous damage, the different types of cell death induced by oxidative stress will be investigated in cells with different defects in DNA repair, searching cellular different responses, that may mimic the different clinical phenotypes observed in patients with neurodegeneration/premature aging. In this project we also intend to investigate the cellular processes that allow the replication of damaged genome. Approaches of next-generation sequencing (NGS) are proposed for studies of mutagenesis and also the identification of mutations and molecular diagnosis of Brazilian patients with XP or other DNA repair related diseases. These studies can provide interesting data on the causes of certain clinical phenotypes, and help patients and their families, with the recognition of the disease, made possible by the molecular diagnosis. XP patients include those from the region of Goiás, due to the high frequency of XP patients observed in Faina, where the incidence is the highest in the world due to geographical isolation and consanguineous marriage. Yet, this project also intends to study how human cells respond to anti-tumor chemotherapeutic agents, aiming to understand the repair mechanisms involved in the repair of DNA damage induced by them and seeking alternative therapies that may enhance the fight against cancer. Finally, we also plan to study genes related to DNA repair in bacteria of basic (Caulobacter crescentus) or medical (Pseudomonas aeruginosa) interest. In the first case, it is an excellent model for studies of bacterial genetics, and we will continue to identify the function of new genes involved in the response to DNA damage. With the model of P. aeruginosa, we aim to investigate the involvement of DNA repair and damage tolerance genes in the responses to antimicrobial compounds, as well as mutagenesis that leads to the emergence of antibiotic resistance. (AU)

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Scientific publications (38)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MUNFORD, V.; CASTRO, L. P.; SOUTO, R.; LERNER, L. K.; VILAR, J. B.; QUAYLE, C.; ASIF, H.; SCHUCH, A. P.; DE SOUZA, T. A.; IENNE, S.; et al. A genetic cluster of patients with variant xeroderma pigmentosum with two different founder mutations. British Journal of Dermatology, v. 176, n. 5, p. 1270-1278, . (13/08028-1, 14/15982-6)
SCHUCH, ANDRE PASSAGLIA; MORENO, NATALIA CESTARI; SCHUCH, NATIELEN JACQUES; MARTINS MENCK, CARLOS FREDERICO; MACHADO GARCIA, CAMILA CARRIAO. Sunlight damage to cellular DNA: Focus on oxidatively generated lesions. Free Radical Biology and Medicine, v. 107, p. 110-124, . (13/08028-1, 14/15982-6)
GOMES, LUCIANA R.; VESSONI, ALEXANDRE T.; MENCK, CARLOS F. M.. Microenvironment and autophagy cross-talk: Implications in cancer therapy. PHARMACOLOGICAL RESEARCH, v. 107, p. 300-307, . (13/08028-1, 14/15982-6)
PEDROSO, JOSE LUIZ; MUNFORD, VERIDIANA; BASTOS, ANDRE UCHIMURA; DE CASTRO, LIGIA PEREIRA; MARUSSI, VICTOR HUGO ROCHA; SILVA, GISELE SAMPAIO; ARITA, JULIANA HARUMI; MENCK, CARLOS F. M.; BARSOTTINI, ORLANDO G.. LMNB1 mutation causes cerebellar involvement and a genome instability defect. JOURNAL OF THE NEUROLOGICAL SCIENCES, v. 379, p. 249-252, . (14/15982-6, 13/21075-9)
FORTUNATO, RODRIGO S.; GOMES, LUCIANA R.; MUNFORD, VERIDIANA; PESSOA, CAROLINA FITTIPALDI; QUINET, ANNABEL; HECHT, FABIO; KAJITANI, GUSTAVO S.; MILITO, CRISTIANE BEDRAN; CARVALHO, DENISE P.; MARTINS MENCK, CARLOS FREDERICO. DUOX1 Silencing in Mammary Cell Alters the Response to Genotoxic Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, . (14/15982-6, 13/21075-9)
MARTINS-PINHEIRO, MARINALVA; OLIVEIRA, ALICE R.; VALENCIA, ALEXY O.; FERNANDEZ-SILVA, FRANK S.; SILVA, LARISSA G.; LOPES-KULISHEV, CARINA O.; ITALIANI, VALERIA C. S.; MARQUES, MARILIS V.; MENCK, CARLOS F.; GALHARDO, RODRIGO S.. Molecular characterization of Caulobacter crescentus mutator strains. Gene, v. 626, p. 251-257, . (14/15982-6)
LERNER, LETICIA K.; FRANCISCO, GUILHERME; SOLTYS, DANIELA T.; ROCHA, CLARISSA R. R.; QUINET, ANNABEL; VESSONI, ALEXANDRE T.; CASTRO, LIGIA P.; DAVID, TAYNAH I. P.; BUSTOS, SILVINA O.; STRAUSS, BRYAN E.; et al. Predominant role of DNA polymerase eta and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells. Nucleic Acids Research, v. 45, n. 3, p. 1270-1280, . (14/15982-6, 13/21075-9)
QUINET, ANNABEL; MARTINS, DAVI JARDIM; VESSONI, ALEXANDRE TEIXEIRA; BIARD, DENIS; SARASIN, ALAIN; STARY, ANNE; MARTINS MENCK, CARLOS FREDERICO. Translesion synthesis mechanisms depend on the nature of DNA damage in UV-irradiated human cells. Nucleic Acids Research, v. 44, n. 12, p. 5717-5731, . (13/08028-1, 14/15982-6)
VESSONI, ALEXANDRE TEIXEIRA; QUINET, ANNABEL; DE ANDRADE-LIMA, LEONARDO CARMO; MARTINS, DAVI JARDIM; MACHADO GARCIA, CAMILA CARRIAO; REILY ROCHA, CLARISSA RIBEIRO; VIEIRA, DEBORA BRAGA; MARTINS MENCK, CARLOS FREDERICO. Chloroquine-induced glioma cells death is associated with mitochondrial membrane potential loss, but not oxidative stress. Free Radical Biology and Medicine, v. 90, p. 91-100, . (14/15982-6)
MELO-HANCHUK, TALITA DINIZ; SLEPICKA, PRISCILA FERREIRA; PELEGRINI, ALESSANDRA LUIZA; MARTINS MENCK, CARLOS FREDERICO; KOBARG, JORG. NEK5 interacts with topoisomerase II beta and is involved in the DNA damage response induced by etoposide. Journal of Cellular Biochemistry, v. 120, n. 10, p. 16853-16866, . (14/15982-6, 17/03489-1, 10/51730-0, 15/06458-4, 10/16831-0, 10/15262-2)
RODRIGUEZ-ROSADO, ANA I.; VALENCIA, ESTELA YNES; RODRIGUEZ-ROJAS, ALEXANDRO; COSTAS, COLOMA; GALHARDO, RODRIGO S.; RODRIGUEZ-BELTRAN, JERONIMO; BLAZQUEZ, JESUS. N-acetylcysteine blocks SOS induction and mutagenesis produced by fluoroquinolones in Escherichia coli. Journal of Antimicrobial Chemotherapy, v. 74, n. 8, p. 2188-2196, . (14/15982-6)
MORENO, NATALIA CESTARI; MACHADO GARCIA, CAMILA CARRIAO; MUNFORD, VERIDIANA; REILY ROCHA, CLARISSA RIBEIRO; PELEGRINI, ALESSANDRA LUIZA; CORRADI, CAMILA; SARASIN, ALAIN; MARTINS MENCK, CARLOS FREDERICO. The key role of UVA-light induced oxidative stress in human Xeroderma Pigmentosum Variant cells. Free Radical Biology and Medicine, v. 131, p. 432-442, . (14/15982-6, 12/16929-6)
MELO, UIRA SOUTO; BONNER, DEVON; KENT LLOYD, KEVIN C.; MOSHIRI, ALA; WILLIS, BRANDON; LANOUE, LOUISE; BOWER, LYNETTE; LEONARD, BRIAN C.; MARTINS, DAVI JARDIM; GOMES, FERNANDO; et al. Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay. Genetics in Medicine, v. 23, n. 4, . (14/15982-6, 13/08028-1, 16/14517-3)
SILVA, MATHEUS MOLINA; REILY ROCHA, CLARISSA RIBEIRO; KINKER, GABRIELA SARTI; PELEGRINI, ALESSANDRA LUIZA; MARTINS MENCK, CARLOS FREDERICO. The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells. SCIENTIFIC REPORTS, v. 9, . (14/15982-6, 15/15184-5, 13/08028-1, 17/24217-0)
FERNANDEZ-SILVA, FRANK S.; SCHULZ, MARIANE L.; ALVES, INGRID REALE; FREITAS, RUBIA R.; DA ROCHA, RAQUEL PAES; LOPES-KULISHEV, CARINA O.; MEDEIROS, MARISA H. G.; GALHARDO, RODRIGO S.. Contribution of GO System Glycosylases to Mutation Prevention in Caulobacter crescentus. Environmental and Molecular Mutagenesis, v. 61, n. 2, . (14/15982-6, 13/07937-8)
SANTIAGO, K. M.; CASTRO, L. P.; NETO, J. P. D.; DE NOBREGA, A. F.; PINTO, C. A. L.; ASHTON-PROLLA, P.; PINTO E VAIRO, F.; DE MEDEIROS, V, P. F.; RIBEIRO, E. M.; RIBEIRO, B. F. R.; et al. Comprehensive germline mutation analysis and clinical profile in a large cohort of Brazilian xeroderma pigmentosum patients. JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, v. 34, n. 10, . (09/16895-1, 14/15982-6)
DE OLIVEIRA, ANDRESSA PERES; ISSAYAMA, LUIDY KAZUO; BETIM PAVAN, ISADORA CAROLINA; SILVA, FERNANDO RIBACK; MELO-HANCHUK, TALITA DINIZ; SIMABUCO, FERNANDO MOREIRA; KOBARG, JORG. Checking NEKs: Overcoming a Bottleneck in Human Diseases. Molecules, v. 25, n. 8, . (18/14818-9, 17/03489-1, 14/15982-6)
LERNER, LETICIA K.; MORENO, NATALIA C.; ROCHA, CLARISSA R. R.; MUNFORD, VERIDIANA; SANTOS, VALQUIRIA; SOLTYS, DANIELA T.; GARCIA, CAMILA C. M.; SARASIN, ALAIN; MENCK, CARLOS F. M.. XPD/ERCC2 mutations interfere in cellular responses to oxidative stress. MUTAGENESIS, v. 34, n. 4, p. 341-354, . (14/15982-6)
NAMRATA KUMAR; NATÁLIA C. MORENO; BRUNO C. FELTES; CARLOS FM MENCK; BENNETT VAN HOUTEN. Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, . (14/15982-6)
REILY ROCHA, CLARISSA RIBEIRO; SILVA, MATHEUS MOLINA; QUINET, ANNABEL; CABRAL-NETO, JANUARIO BISPO; MARTINS MENCK, CARLOS FREDERICO. DNA repair pathways and cisplatin resistance: an intimate relationship. Clinics, v. 73, n. 1, . (14/15982-6)
KUMAR, NAMRATA; MORENO, NATALIA C.; FELTES, BRUNO C.; MENCK, CARLOS F. M.; VAN HOUTEN, BENNETT. Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, 1, . (14/15982-6)
MORENO, NATALIA CESTARI; DE SOUZA, TIAGO ANTONIO; MACHADO GARCIA, CAMILA CARRIAO; RUIZ, NATHALIA QUINTERO; CORRADI, CAMILA; CASTRO, LIGIA PEREIRA; MUNFORD, VERIDIANA; IENNE, SUSAN; ALEXANDROV, LUDMIL B.; MARTINS MENCK, CARLOS FREDERICO. Whole-exome sequencing reveals the impact of UVA light mutagenesis in xeroderma pigmentosum variant human cells. Nucleic Acids Research, v. 48, n. 4, p. 1941-1953, . (14/15982-6, 12/16929-6, 13/08028-1, 18/06619-6)
CASTRO, L. P.; SAHBATOU, M.; KEHDY, F. S. G.; FARIAS, A. A.; YURCHENKO, A. A.; DE SOUZA, T. A.; ROSA, R. C. A.; MENDES-JUNIOR, C. T.; BORDA, V; MUNFORD, V; et al. The Iberian legacy into a young genetic xeroderma pigmentosum cluster in central Brazil. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, v. 852, n. SI, . (14/15982-6, 13/08028-1)
PERES DE OLIVEIRA, ANDRESSA; BASEI, FERNANDA LUISA; SLEPICKA, PRISCILA FERREIRA; DE CASTRO FEREZIN, CAMILA; MELO-HANCHUK, TALITA D.; DE SOUZA, EDMARCIA ELISA; LIMA, TANES I.; DOS SANTOS, VALQUIRIA TIAGO; MENDES, DAVI; SILVEIRA, LEONARDO REIS; et al. NEK10 interactome and depletion reveal new roles in mitochondria. PROTEOME SCIENCE, v. 18, n. 1, . (14/15982-6, 18/05350-3, 17/03489-1)
QUINET, ANNABEL; LERNER, LETICIA K.; MARTINS, DAVI J.; MENCK, CARLOS F. M.. Filling gaps in translesion DNA synthesis in human cells. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, v. 836, n. B, SI, p. 127-142, . (13/21075-9, 14/15982-6)
GOMES, LUCIANA RODRIGUES; REILY ROCHA, CLARISSA RIBEIRO; MARTINS, DAVI JARDIM; PETISCO FIORE, ANA PAULA ZEN; KINKER, GABRIELA SARTI; BRUNI-CARDOSO, ALEXANDRE; MARTINS MENCK, CARLOS FREDERICO. ATR mediates cisplatin resistance in 3D-cultured breast cancer cells via translesion DNA synthesis modulation. CELL DEATH & DISEASE, v. 10, . (14/25832-1, 14/10492-0, 11/50856-3, 14/15982-6)
VASCONCELOS, RENATA PRADO; PEIXOTO, MILENA SIMOES; DE OLIVEIRA, KECIANY ALVES; FREITAS FERREIRA, ANDREA CLAUDIA; COELHO-DE-SOUZA, ANDRELINA NORONHA; CARVALHO, DENISE P.; DE OLIVEIRA, ARICLECIO CUNHA; FORTUNATO, RODRIGO S.. Sex differences in subcutaneous adipose tissue redox homeostasis and inflammation markers in control and high-fat diet fed rats. APPLIED PHYSIOLOGY NUTRITION AND METABOLISM, v. 44, n. 7, p. 720-726, . (13/21075-9, 14/15982-6)
ALEXY O. VALENCIA; VÂNIA S. BRAZ; MAGNA MAGALHÃES; RODRIGO S. GALHARDO. Role of error-prone DNA polymerases in spontaneous mutagenesis in Caulobacter crescentus. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, . (14/15982-6, 11/09465-0, 10/20780-2)
MARTINS, MARIANA BONJIORNO; PEREZ, ARINA MARINA; BOHR, VILHELM A.; WILSON, III, DAVID M.; KOBARG, JORG. NEK1 deficiency affects mitochondrial functions and the transcriptome of key DNA repair pathways. MUTAGENESIS, v. 36, n. 3, p. 223-236, . (16/02040-8, 14/15982-6, 17/21067-7, 17/03489-1)
GOMES, LUCIANA R.; MENCK, CARLOS F. M.; LEANDRO, GIOVANA S.. Autophagy Roles in the Modulation of DNA Repair Pathways. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 18, n. 11, . (13/08028-1, 14/15982-6)
VALENCIA, ESTELA YNES; ESPOSITO, FERNANDA; SPIRA, BENY; BLAZQUEZ, JESUS; GALHARDO, RODRIGO S.. Ciprofloxacin-Mediated Mutagenesis Is Suppressed by Subinhibitory Concentrations of Amikacin in Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, v. 61, n. 3, . (14/15982-6)
ALVES, NILMARA DE OLIVEIRA; VESSONI, ALEXANDRE TEIXEIRA; QUINET, ANNABEL; FORTUNATO, RODRIGO SOARES; KAJITANI, GUSTAVO SATORU; PEIXOTO, MILENA SIMOES; HACON, SANDRA DE SOUZA; ARTAXO, PAULO; SALDIVA, PAULO; MARTINS MENCK, CARLOS FREDERICO; et al. Biomass burning in the Amazon region causes DNA damage and cell death in human lung cells. SCIENTIFIC REPORTS, v. 7, . (13/05014-0, 14/15982-6, 14/02297-3)
REILY ROCHA, CLARISSA RIBEIRO; KAJITANI, GUSTAVO SATORU; QUINET, ANNABEL; FORTUNATO, RODRIGO SOARES; MARTINS MENCK, CARLOS FREDERICO. NRF2 and glutathione are key resistance mediators to temozolomide in glioma and melanoma cells. ONCOTARGET, v. 7, n. 30, p. 48081-48092, . (13/08028-1, 14/15982-6)
GOMES, LUCIANA R.; MENCK, CARLOS F. M.; CUERVO, ANA MARIA. Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation. AUTOPHAGY, v. 13, n. 5, p. 928-940, . (14/15982-6, 11/50856-3)
MORENO, NATALIA CESTARI; MACHADO GARCIA, CAMILA CARRIAO; REILY ROCHA, CLARISSA RIBEIRO; MUNFORD, VERIDIANA; MARTINS MENCK, CARLOS FREDERICO. ATR/Chk1 Pathway is Activated by Oxidative Stress in Response to UVA Light in Human Xeroderma Pigmentosum Variant Cells. Photochemistry and Photobiology, v. 95, n. 1, p. 345-354, . (12/16929-6, 13/08028-1, 14/15982-6)
ALVES, INGRID R.; LIMA-NORONHA, MARCO A.; SILVA, LARISSA G.; FERNANDEZ-SILVA, FRANK S.; FREITAS, ALINE LUIZA D.; MARQUES, MARILIS V.; GALHARDO, RODRIGO S.. Effect of SOS-induced levels of imuABC on spontaneous and damage-induced mutagenesis in Caulobacter crescentus. DNA Repair, v. 59, p. 20-26, . (13/23133-6, 14/15982-6, 14/04046-8)
YAGURA, TEITI; SCHUCH, ANDRE PASSAGLIA; MACHADO GARCIA, CAMILA CARRIAO; REILY ROCHA, CLARISSA RIBEIRO; MORENO, NATALIA CESTARI; FRIEDMANN ANGELI, JOSE PEDRO; MENDES, DAVI; SEVERINO, DIVINOMAR; SANCHEZ, ANGELICA BIANCHINI; DI MASCIO, PAOLO; et al. Direct participation of DNA in the formation of singlet oxygen and base damage under UVA irradiation. Free Radical Biology and Medicine, v. 108, p. 86-93, . (12/12663-1, 13/07937-8, 14/15982-6, 13/08028-1)
MASUDA, HANA PAULA; NAKABASHI, MYNA; MORGANTE, PATRICIA G.; KAJIHARA, DANIELA; DE SETTA, NATHALIA; MARTINS MENCK, CARLOS FREDERICO; VAN SLUYS, MARIE-ANNE. Evidence for sub-functionalization of tandemly duplicated XPB nucleotide excision repair genes in Arabidopsis thaliana. Gene, v. 754, . (14/15982-6, 09/52417-7)

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