PMID: 26811421 RLIMS-P 2 Check other iTextMine results Issue Report
Title
| 1. | TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity. |
Abstract
| 2. | Topoisomerase IIβ-binding protein 1 (TOPBP1) participates in DNA replication and DNA damage response; however, its role in DNA repair and relevance for human cancer remain unclear. |
| 3. | Here, through an unbiased small interfering RNA screen, we identified and validated TOPBP1 as a novel determinant whose loss sensitized human cells to olaparib, an inhibitor of poly(ADP-ribose) polymerase. |
| 4. | We show that TOPBP1 acts in homologous recombination (HR) repair, impacts olaparib response, and exhibits aberrant patterns in subsets of human ovarian carcinomas. |
| 5. | TOPBP1 depletion abrogated RAD51 loading to chromatin and formation of RAD51 foci, but without affecting the upstream HR steps of DNA end resection and RPA loading. |
| 6. | Furthermore, TOPBP1 BRCT domains 7/8 are essential for RAD51 foci formation. |
| 7. | Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin. |
| 8. | Overall, our results provide mechanistic insights into TOPBP1's role in HR, with potential clinical implications for cancer treatment. |
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