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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
Principal Investigator: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
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
17/14833-5 - Nucleotide Excision Repair roles in R-loops accumulation and telomere maintenance in human cells, BP.PD
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
16/25784-2 - Resistance mechanisms to treatment with temozolomide in glioma cells, BP.PD
17/05680-0 - Mechanisms of translesion synthesis in human cells, BP.DD
17/01760-0 - Investigating the involvement of genome lesions and DNA repair in cells infected by Trypanosoma Cruzi, BP.PD
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)

Articles published in Agência FAPESP about the research grant
Study helps improve efficacy of treatment for brain and skin cancer 

Scientific publications (19)
(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)
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, FEB 1 2019. Web of Science Citations: 0.
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, JAN 2019. Web of Science Citations: 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, DEC 2018. Web of Science Citations: 0.
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, 2018. Web of Science Citations: 0.
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 2018. Web of Science Citations: 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, NOV 2017. Web of Science Citations: 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 NOV 2017. Web of Science Citations: 11.
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; BATISTUZZO DE MEDEIROS, SILVIA REGINA. Biomass burning in the Amazon region causes DNA damage and cell death in human lung cells. SCIENTIFIC REPORTS, v. 7, SEP 7 2017. Web of Science Citations: 8.
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, AUG 30 2017. Web of Science Citations: 0.
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; GENNARI DE MEDEIROS, MARISA HELENA; MARTINS MENCK, CARLOS FREDERICO. 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, JUL 2017. Web of Science Citations: 4.
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, JUN 2017. Web of Science Citations: 41.
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.; ALVES, F. I. A.; MOURA, L. M. S.; GALANTE, P. A. F.; CAMARGO, A. A.; LIBOREDO, R.; PENA, S. D. J.; SARASIN, A.; CHAIBUB, S. C.; MENCK, C. F. M. 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, MAY 2017. Web of Science Citations: 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 MAR 2017. Web of Science Citations: 1.
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.; GOTTIFREDI, VANESA; STARY, ANNE; SARASIN, ALAIN; CHAMMAS, ROGER; MENCK, CARLOS F. M. 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, FEB 2017. Web of Science Citations: 10.
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, 2017. Web of Science Citations: 12.
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, JUL 26 2016. Web of Science Citations: 22.
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, JUL 8 2016. Web of Science Citations: 10.
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, MAY 2016. Web of Science Citations: 17.
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, JAN 2016. Web of Science Citations: 8.

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