DNA-PKcs and PARP1 bind to unresected stalled DNA replication forks where they recruit XRCC1 to mediate repair
| Autor: | Joanna F. McGouran, Xinming Song, Zhengqiang Bao, Freddie C. Hamdy, Huahao Shen, Katheryn Meek, Annette L. Medhurst, Songmin Ying, Jessica A. Neal, Oliver Mortusewicz, Zhihui Chen, Benedikt M. Kessler, Thomas Helleday |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
DNA re-replication DNA Replication Cancer Research DNA Repair Poly (ADP-Ribose) Polymerase-1 Eukaryotic DNA replication DNA-Activated Protein Kinase Biology Article Cell Line 03 medical and health sciences Replication factor C Minichromosome maintenance Control of chromosome duplication Humans Casein Kinase II Replication protein A Genetics MRE11 Homologue Protein DNA replication Nuclear Proteins Cell biology DNA-Binding Proteins enzymes and coenzymes (carbohydrates) 030104 developmental biology X-ray Repair Cross Complementing Protein 1 Oncology Origin recognition complex Poly(ADP-ribose) Polymerases |
| Zdroj: | Europe PubMed Central |
| DOI: | 10.1158/0008-5472.can-15-0608 |
| Popis: | A series of critical pathways are responsible for the detection, signaling, and restart of replication forks that encounter blocks during S-phase progression. Small base lesions may obstruct replication fork progression and processing, but the link between repair of small lesions and replication forks is unclear. In this study, we investigated a hypothesized role for DNA-PK, an important enzyme in DNA repair, in cellular responses to DNA replication stress. The enzyme catalytic subunit DNA-PKcs was phosphorylated on S2056 at sites of stalled replication forks in response to short hydroxyurea treatment. Using DNA fiber experiments, we found that catalytically active DNA-PK was required for efficient replication restart of stalled forks. Furthermore, enzymatically active DNA-PK was also required for PARP-dependent recruitment of XRCC1 to stalled replication forks. This activity was enhanced by preventing Mre11-dependent DNA end resection, suggesting that XRCC1 must be recruited early to an unresected stalled fork. We also found that XRCC1 was required for effective restart of a subset of stalled replication forks. Overall, our work suggested that DNA-PK and PARP-dependent recruitment of XRCC1 is necessary to effectively protect, repair, and restart stalled replication forks, providing new insight into how genomic stability is preserved. Cancer Res; 76(5); 1078–88. ©2015 AACR. |
| Databáze: | OpenAIRE |
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