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Myung, Kyungjae
Center for Genomic Integrity
Research Interests
  • DNA Replication, DNA Repair, DNA Recombination, DNA Damage Response, cancer, aging

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Timely termination of repair DNA synthesis by ATAD5 is important in oxidative DNA damage-induced single-strand break repair

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Title
Timely termination of repair DNA synthesis by ATAD5 is important in oxidative DNA damage-induced single-strand break repair
Author
Park, Su HyungKim, YouyoungRa, Jae SunWie, Min WooKang, Mi-SunKang, SukhyunMyung, KyungjaeLee, Kyoo-young
Issue Date
2021-11
Publisher
OXFORD UNIV PRESS
Citation
NUCLEIC ACIDS RESEARCH, v.49, no.20, pp.11746 - 11764
Abstract
Reactive oxygen species (ROS) generate oxidized bases and single-strand breaks (SSBs), which are fixed by base excision repair (BER) and SSB repair (SSBR), respectively. Although excision and repair of damaged bases have been extensively studied, the function of the sliding clamp, proliferating cell nuclear antigen (PCNA), including loading/unloading, remains unclear. We report that, in addition to PCNA loading by replication factor complex C (RFC), timely PCNA unloading by the ATPase family AAA domain-containing protein 5 (ATAD5)-RFC-like complex is important for the repair of ROS-induced SSBs. We found that PCNA was loaded at hydrogen peroxide (H2O2)-generated direct SSBs after the 3'-terminus was converted to the hydroxyl moiety by end-processing enzymes. However, PCNA loading rarely occurred during BER of oxidized or alkylated bases. ATAD5-depleted cells were sensitive to acute H2O2 treatment but not methyl methanesulfonate treatment. Unexpectedly, when PCNA remained on DNA as a result of ATAD5 depletion, H2O2-induced repair DNA synthesis increased in cancerous and normal cells. Based on higher H2O2-induced DNA breakage and SSBR protein enrichment by ATAD5 depletion, we propose that extended repair DNA synthesis increases the likelihood of DNA polymerase stalling, shown by increased PCNA monoubiquitination, and consequently, harmful nick structures are more frequent.
URI
https://scholarworks.unist.ac.kr/handle/201301/56588
URL
https://academic.oup.com/nar/article/49/20/11746/6414590
DOI
10.1093/nar/gkab999
ISSN
0305-1048
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