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Effect of UVA light in cells from patients with variant Xeroderma pigmentosum

Grant number: 12/16929-6
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2013
Effective date (End): June 30, 2017
Field of knowledge:Biological Sciences - Genetics - Mutagenesis
Principal Investigator:Carlos Frederico Martins Menck
Grantee:Natália Cestari Moreno
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:09/52417-7 - Cell responses to genome damage, AP.TEM


The DNA molecule is constantly exposed to the physical (like UV light) and chemical agents (such as chemotherapy or reactive oxygen species and/or nitrogen) that can cause lesions. Such lesions can interfere with important cell processes such as DNA replication and RNA transcription, which can result in mutations or cell death. Ultraviolet light (UV) is indeed a genotoxic environmental agent. In the UV spectrum (UVC: 200-280nm, UVB: 280-315nm and UVA: 315-400nm), UVA light which is considered to be the most abundant in the earth's surface (about 90%), then the UVC and UVB, is harmful to DNA, proteins and lipids and may participate in the induction of skin cancer. The damage caused by UV light can result in photolesion through direct absorption by the DNA, such as cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone (6-4 PPs). Alternatively, photosensitizers excited by UV light can result in oxidized bases mediated by singlet oxygen (1O2) or other oxygen radicals in which the main product formed is 8-oxo-7, 8-dihidroguanine (8-oxoG). As a result of these damages, UVA exposure can cause mutations that are the primary causes in tumor formation. Dramatic examples of this relationship (mutation-cancer-lesion) is demonstrated in a rare hereditary syndrome known as Xeroderma pigmentosum (XP), characterized by mutations in one of the seven genes that encode proteins (XP-A to G) that participate in the Nucleotide Excision Repair (NER - Nucleotide Excision Repair) and a variant group (XP-V) encoding the DNA polymerase (pol eta) which catalyze translesion synthesis (TLS) of UV induced DNA damage. The proportion of people affected with XP is about one in each hundred thousand inhabitants, but in a community in the state of Goiás more than twenty patients in a population of about one thousand inhabitants were diagnosed. Preliminary data observed by our group indicates that these patients have mutations in the POLH gene encoding the pol eta, and are diagnosed as XP-V. Considering the importance of understanding the mechanisms of UVA induced lesions in the DNA molecule and its mutagenic after effects, this project aims to verify the direct and/or indirect damages in the DNA molecule caused by UVA light and the types of mutations generated in the genome of XP-V cells, as well as in cells of Goiás patients, to characterize the profile of mutations of these cells and to identify mutations which contribute to the classic phenotype observed in these patients. The characterization of these UVA irradiated mutagenesis will be performed using classic techniques of mutation detection (the HPRT gene) and by exome sequencing. (AU)

Scientific publications
(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; 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, FEB 28 2020. Web of Science Citations: 0.
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: 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, JAN 2019. Web of Science Citations: 1.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
MORENO, Natália Cestari. Effects of UVA light on Xeroderma Pigmentosum Variant patient cells. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Biociências São Paulo.

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