title: Aberrant base excision repair pathway of oxidatively damaged DNA: Implications for degenerative diseases.
abstract: In cellular organisms composition of DNA is constrained to only four nucleobases A, G, T and C, except for minor DNA base modifications such as methylation which serves for defence against foreign DNA or gene expression regulation. Interestingly, this severe evolutionary constraint among other things demands DNA repair systems to discriminate between regular and modified bases. 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, in DNA repair deficient cells bacterial MutY, human TDG and mammalian MMR can act in the aberrant manner: MutY 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 unrepaired DNA lesions. Evidences accumulated showing that in addition to the accumulation of oxidatively damaged DNA in cells, the aberrant DNA repair can also contribute to cancer, brain disorders and premature senescence. For example, the aberrant BER and MMR pathways for oxidized guanine residues can lead to trinucleotide expansion that underlies Huntington's disease, a severe hereditary neurodegenerative syndrome. This review summarises the present knowledge about the aberrant DNA repair pathways for oxidized base modifications and their possible role in age-related diseases.
authors.affiliation: Groupe «Réparation de l'ADN», Equipe Labellisée par la Ligue Nationale Contre le Cancer, CNRS UMR8200, Université Paris-Sud, Gustave Roussy Cancer Campus, F-94805 Villejuif Cedex, France.
authors.forename: Ibtissam
authors.initials: I
authors.lastname: Talhaoui
authors.affiliation: National laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan.
authors.forename: Bakhyt T
authors.initials: BT
authors.lastname: Matkarimov
authors.affiliation: LBPA, UMR8113 ENSC - CNRS, Ecole Normale Supérieure de Cachan, Cachan, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Tchenio
authors.affiliation: SB RAS Institute of Chemical Biology and Fundamental Medicine, Novosibirsk 630090, Russia; Novosibirsk State University, Novosibirsk 630090, Russia.
authors.forename: Dmitry O
authors.initials: DO
authors.lastname: Zharkov
authors.affiliation: Groupe «Réparation de l'ADN», Equipe Labellisée par la Ligue Nationale Contre le Cancer, CNRS UMR8200, Université Paris-Sud, Gustave Roussy Cancer Campus, F-94805 Villejuif Cedex, France. Electronic address: murat.saparbaev@gustaveroussy.fr.
authors.forename: Murat K
authors.initials: MK
authors.lastname: Saparbaev
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010084:Oxidation-Reduction; D018384:Oxidative Stress
chemical_list: D004247:DNA
keywords: 8-oxo-7,8-dihydroguanine, purine 8,5′-cyclo-2′-deoxyribonucleosides, base excision repair; AP endonuclease; DNA glycosylase, nucleotide incision repair; Mismatch repair; Nucleotide excision repair, trinucleotide expansion; Oxidatively damaged DNA