53BP1/Rif1/Shieldin counteract DSB resection through CST/Polα-dependent fill-in
| Autor: | Francisca Lottersberger, Daniel Durocher, Tatsuya Kibe, Kaori K. Takai, Titia de Lange, Hiroyuki Takai, Alessandro Bianchi, Michal Zimmermann, Zachary Mirman, Yi Gong |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
DNA repair DNA damage PARPi Telomere-Binding Proteins RAD51 Poly (ADP-Ribose) Polymerase-1 DNA Single-Stranded DNA Primase Article Cell Line 03 medical and health sciences chemistry.chemical_compound Mice PARP1 Rif1 Animals Humans DNA Breaks Double-Stranded fill-in synthesis Replication protein A Polymerase Shieldin CST Multidisciplinary biology Effector BRCA1 Protein Recombinational DNA Repair Telomere BRCA1 DNA Polymerase I 53BP1 3. Good health Cell biology enzymes and coenzymes (carbohydrates) 030104 developmental biology chemistry Multiprotein Complexes biology.protein 5′ end resection Tumor Suppressor p53-Binding Protein 1 DNA Polymerase α/primase |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | In DNA repair, the resection of double-strand breaks dictates the choice between homology-directed repair—which requires a 3′ overhang—and classical non-homologous end joining, which can join unresected ends1,2. BRCA1-mutant cancers show minimal resection of double-strand breaks, which renders them deficient in homology-directed repair and sensitive to inhibitors of poly(ADP-ribose) polymerase 1 (PARP1)3–8. When BRCA1 is absent, the resection of double-strand breaks is thought to be prevented by 53BP1, RIF1 and the REV7–SHLD1–SHLD2–SHLD3 (shieldin) complex, and loss of these factors diminishes sensitivity to PARP1 inhibitors4,6–9. Here we address the mechanism by which 53BP1–RIF1–shieldin regulates the generation of recombinogenic 3′ overhangs. We report that CTC1–STN1–TEN1 (CST)10, a complex similar to replication protein A that functions as an accessory factor of polymerase-α (Polα)–primase11, is a downstream effector in the 53BP1 pathway. CST interacts with shieldin and localizes with Polα to sites of DNA damage in a 53BP1- and shieldin-dependent manner. As with loss of 53BP1, RIF1 or shieldin, the depletion of CST leads to increased resection. In BRCA1-deficient cells, CST blocks RAD51 loading and promotes the efficacy of PARP1 inhibitors. In addition, Polα inhibition diminishes the effect of PARP1 inhibitors. These data suggest that CST–Polα-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1 and shieldin. |
| Databáze: | OpenAIRE |
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