Timely termination of repair DNA synthesis by ATAD5 is important in oxidative DNA damage-induced single-strand break repair
| Autor: | Jae Sun Ra, Min Woo Wie, Kyungjae Myung, Youyoung Kim, Mi-Sun Kang, Sukhyun Kang, KS Lee, Su Hyung Park |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
DNA Replication
DNA End-Joining Repair DNA polymerase DNA damage AcademicSubjects/SCI00010 Genome Integrity Repair and Replication chemistry.chemical_compound Proliferating Cell Nuclear Antigen Genetics Humans DNA clamp biology DNA synthesis Base excision repair Hydrogen Peroxide Proliferating cell nuclear antigen Cell biology Methyl methanesulfonate DNA-Binding Proteins Oxidative Stress HEK293 Cells chemistry biology.protein ATPases Associated with Diverse Cellular Activities DNA HeLa Cells |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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