Aberrant base excision repair pathway of oxidatively damaged DNA: Implications for degenerative diseases

Ibtissam Talhaoui, Bakhyt T. Matkarimov, Thierry Tchenio, Dmitry O. Zharkov, Murat K. Saparbaev

Research output: Contribution to journalReview article

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)266-277
Number of pages12
JournalFree Radical Biology and Medicine
Volume107
DOIs
Publication statusPublished - Jun 1 2017

Fingerprint

DNA Repair
Repair
DNA
DNA Mismatch Repair
Thymine
Adenine
Genomic Instability
Thymine DNA Glycosylase
DNA Repair-Deficiency Disorders
5-Methylcytosine
DNA Glycosylases
Huntington Disease
Guanine
Gene Expression Regulation
Brain Diseases
Gene expression regulation
DNA-Directed DNA Polymerase
Brain Neoplasms
Base Pairing
Genes

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Aberrant base excision repair pathway of oxidatively damaged DNA : Implications for degenerative diseases. / Talhaoui, Ibtissam; Matkarimov, Bakhyt T.; Tchenio, Thierry; Zharkov, Dmitry O.; Saparbaev, Murat K.

In: Free Radical Biology and Medicine, Vol. 107, 01.06.2017, p. 266-277.

Research output: Contribution to journalReview article

Talhaoui, Ibtissam ; Matkarimov, Bakhyt T. ; Tchenio, Thierry ; Zharkov, Dmitry O. ; Saparbaev, Murat K. / Aberrant base excision repair pathway of oxidatively damaged DNA : Implications for degenerative diseases. In: Free Radical Biology and Medicine. 2017 ; Vol. 107. pp. 266-277.
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