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The role of ERCC1 and XPF in replicative stress and genetic instability

Grant number: 16/17121-3
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): December 01, 2016
Effective date (End): November 30, 2017
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Carlos Frederico Martins Menck
Grantee:Alessandra Luiza Pelegrini
Supervisor abroad: Jean-Sébastien Hoffmann
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : Centre de Recherche en Cancérologie de Toulouse (CRCT), France  
Associated to the scholarship:14/04157-4 - Modulating the activity of DNA repair proteins to improve chemotherapy effects, BP.PD

Abstract

Cancer is currently the leading cause of morbidity and mortality worldwide which it is characterized by abnormal and uncontrolled cell growth in addition to genetic instability. The disease starts and progresses mainly through failed attempts at replication of the genome by the cell as well as inaccuracies in segregating that information between its daughter cells. During the replication, the fork can be stalled for several reasons, such as DNA damage, structured DNA, nucleotide depletion and encounters with the transcription machinery, characterizing replication stress. It is well established that replication stress contributes to chromosomal instability since stalled forks may eventually collapse, producing a broken DNA end. Up until recently, fork collapse was only thought to happen after prolonged (24 hours) DNA replication stress. However, results obtained by Prof. Jean-Sébastien Hoffmann group show that fork collapse can be an early event after replication stress induction and it is dependent on XPF activity (T Goullet de Rugy , R Bétous and JS Hoffmann, submitted). In my postdoc project, I have investigated the role of that endonuclease and its partner, ERCC1, in interstrand crosslink (ICLs) repair and its evolvement in chemotherapy sensitivity. Since the ICLs may cause persistent fork stalling, the proposed objective for this research in collaboration with Professor Hoffmann's group is understanding how the XPF-ERCC1 complex and each of these separate protein participate in DNA replication stress, exploring their roles from the regulation of fork collapse to repair mechanisms, and evaluating the importance of these early events in the development of genetic instability from chromosomal aberrations. To achieve that, I shall use knockout cell lineages for XPF and ERCC1 obtained by the CRISPR/Cas 9 technique in the first years of my post-doctoral project. It is expected to obtain important data for understanding the early replication stress response and how it may favor the emergence of genetic instability in the context of DNA damage and Cancer. (AU)