UMR INSERM U1242-OSS SPECIAL SEMINAR - Centre De Lutte Contre Le Cancer Eugène Marquis

Study of the aberrant base excision repair pathway of oxidatively damaged DNA: implications for mutagenesis and evolution

Dr. Murat SAPARBAEV

UMR9019 CNRS – Gustave Roussy Cancer Campus – Univ Paris-Saclay

DNA repair, ADP-ribosylation and Cancer Team

Abstract

Cellular organisms must constantly contend with endogenous DNA damage caused by oxidative stress and have evolved multiple DNA repair systems to deal with these insults. DNA repair systems can usually discriminate between regular and modified bases. For example, DNA glycosylases specifically recognize and excise damaged bases among vast majority of regular bases in the base excision repair (BER) pathway. However, the mismatched base pairs in DNA can occur from a spontaneous conversion of 5-methylcytosine to thymine and DNA polymerase errors during replication. To counteract these mutagenic threats to genome stability, cells evolved special DNA repair systems that target the non-damaged DNA strand in a duplex to remove mismatched regular DNA bases. Mismatch-specific adenine- and thymine-DNA glycosylases (MutY/MUTYH and TDG/MBD4, respectively) initiated BER and mismatch repair (MMR) pathways can recognize and remove normal DNA bases in mismatched DNA duplexes. Importantly, under certain circumstances human MUTYH and TDG and mammalian MMR can act in the aberrant manner: MutY/MUTYH and TDG removes adenine and thymine opposite misincorporated 8-oxoguanine and damaged adenine, respectively, whereas MMR removes thymine opposite to O6-methylguanine. These unusual activities lead either to mutations or futile DNA repair, thus indicating that the DNA repair pathways which target non-damaged DNA strand can act in aberrant manner and introduce genome instability in the presence of persistent unrepaired DNA lesions. Here I would talk about aberrant base excision repair and its possible role in mutagenesis, age-related diseases and evolution.