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XRCC1 prevents toxic PARP1 trapping during DNA base excision repair
AA. Demin, K. Hirota, M. Tsuda, M. Adamowicz, R. Hailstone, J. Brazina, W. Gittens, I. Kalasova, Z. Shao, S. Zha, H. Sasanuma, H. Hanzlikova, S. Takeda, KW. Caldecott
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
694996
European Research Council - International
MR/P010121/1
Medical Research Council - United Kingdom
R01 CA226852
NCI NIH HHS - United States
NLK
Cell Press Free Archives
od 1997-12-01 do Před 1 rokem
Free Medical Journals
od 1997 do Před 1 rokem
Free Medical Journals
od 1997 do Před 1 rokem
Open Access Digital Library
od 1997-12-01
Elsevier Open Access Journals
od 1997-12-01 do 2023-06-15
Elsevier Open Archive Journals
od 1997-12-01 do Před 1 rokem
- MeSH
- buněčné linie MeSH
- DNA vazebné proteiny metabolismus MeSH
- DNA-ligasa ATP metabolismus MeSH
- DNA-polymerasa beta metabolismus MeSH
- DNA genetika MeSH
- fibroblasty účinky léků metabolismus MeSH
- jednořetězcové zlomy DNA MeSH
- lidé MeSH
- oprava DNA účinky léků genetika MeSH
- PARP inhibitory farmakologie MeSH
- poly-ADP-ribóza-polymeráza 1 metabolismus MeSH
- poly(ADP-ribosa)-polymerasy metabolismus MeSH
- poškození DNA účinky léků genetika MeSH
- protein XRCC1 metabolismus MeSH
- vazba proteinů účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Mammalian DNA base excision repair (BER) is accelerated by poly(ADP-ribose) polymerases (PARPs) and the scaffold protein XRCC1. PARPs are sensors that detect single-strand break intermediates, but the critical role of XRCC1 during BER is unknown. Here, we show that protein complexes containing DNA polymerase β and DNA ligase III that are assembled by XRCC1 prevent excessive engagement and activity of PARP1 during BER. As a result, PARP1 becomes "trapped" on BER intermediates in XRCC1-deficient cells in a manner similar to that induced by PARP inhibitors, including in patient fibroblasts from XRCC1-mutated disease. This excessive PARP1 engagement and trapping renders BER intermediates inaccessible to enzymes such as DNA polymerase β and impedes their repair. Consequently, PARP1 deletion rescues BER and resistance to base damage in XRCC1-/- cells. These data reveal excessive PARP1 engagement during BER as a threat to genome integrity and identify XRCC1 as an "anti-trapper" that prevents toxic PARP1 activity.
Department of Chemistry Tokyo Metropolitan University Minami Osawa Hachioji shi Tokyo 192 0397 Japan
Citace poskytuje Crossref.org
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