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53BP1-RIF1-shieldin...
53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polα-dependent fill-in.
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- Mirman, Zachary (författare)
- Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA.
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- Lottersberger, Francisca (författare)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA.
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- Takai, Hiroyuki (författare)
- Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA.
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- Kibe, Tatsuya (författare)
- Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA.
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- Gong, Yi (författare)
- Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA.
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- Takai, Kaori (författare)
- Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA.
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- Bianchi, Alessandro (författare)
- Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA.; Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK.
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- Zimmermann, Michal (författare)
- Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA.; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
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- Durocher, Daniel (författare)
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
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- de Lange, Titia (författare)
- Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA. delange@rockefeller.edu.
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Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA Avdelningen för läkemedelsforskning (creator_code:org_t)
- 2018-07-18
- 2018
- Engelska.
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Ingår i: Nature. - : Springer. - 0028-0836 .- 1476-4687. ; 560:7716, s. 112-116
- Relaterad länk:
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
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Mirman, Zachary
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Lottersberger, F ...
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Takai, Hiroyuki
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Kibe, Tatsuya
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Gong, Yi
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Takai, Kaori
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Bianchi, Alessan ...
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Zimmermann, Mich ...
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Durocher, Daniel
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de Lange, Titia
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