p31comet promotes homologous recombination by inactivating REV7 through the TRIP13 ATPase
Copyright © 2020 the Author(s). Published by PNAS..
The repair of DNA double strand breaks (DSBs) that arise from external mutagenic agents and routine cellular processes is essential for life. DSBs are repaired by two major pathways, homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). DSB repair pathway choice is largely dictated at the step of 5'-3' DNA end resection, which is promoted during S phase, in part by BRCA1. Opposing end resection is the 53BP1 protein, which recruits the ssDNA-binding REV7-Shieldin complex to favor C-NHEJ repair. We recently identified TRIP13 as a proresection factor that remodels REV7, causing its dissociation from the Shieldin subunit SHLD3. Here, we identify p31comet, a negative regulator of MAD2 and the spindle assembly checkpoint, as an important mediator of the TRIP13-REV7 interaction. p31comet binds to the REV7-Shieldin complex in cells, promotes REV7 inactivation, and causes PARP inhibitor resistance. p31comet also participates in the extraction of REV7 from the chromatin. Furthermore, p31comet can counteract REV7 function in translesion synthesis (TLS) by releasing it from REV3 in the Pol ζ complex. Finally, p31comet, like TRIP13, is overexpressed in many cancers and this correlates with poor prognosis. Thus, we reveal a key player in the regulation of HR and TLS with significant clinical implications.
| Errataetall: |
CommentIn: Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):27761-27763. - PMID 33122436 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:117 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 117(2020), 43 vom: 27. Okt., Seite 26795-26803 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sarangi, Prabha [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.12.2020 Date Revised 17.03.2021 published: Print-Electronic CommentIn: Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):27761-27763. - PMID 33122436 Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2008830117 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316209481 |
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| 100 | 1 | |a Sarangi, Prabha |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a p31comet promotes homologous recombination by inactivating REV7 through the TRIP13 ATPase |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Completed 17.12.2020 | ||
| 500 | |a Date Revised 17.03.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):27761-27763. - PMID 33122436 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 the Author(s). Published by PNAS. | ||
| 520 | |a The repair of DNA double strand breaks (DSBs) that arise from external mutagenic agents and routine cellular processes is essential for life. DSBs are repaired by two major pathways, homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). DSB repair pathway choice is largely dictated at the step of 5'-3' DNA end resection, which is promoted during S phase, in part by BRCA1. Opposing end resection is the 53BP1 protein, which recruits the ssDNA-binding REV7-Shieldin complex to favor C-NHEJ repair. We recently identified TRIP13 as a proresection factor that remodels REV7, causing its dissociation from the Shieldin subunit SHLD3. Here, we identify p31comet, a negative regulator of MAD2 and the spindle assembly checkpoint, as an important mediator of the TRIP13-REV7 interaction. p31comet binds to the REV7-Shieldin complex in cells, promotes REV7 inactivation, and causes PARP inhibitor resistance. p31comet also participates in the extraction of REV7 from the chromatin. Furthermore, p31comet can counteract REV7 function in translesion synthesis (TLS) by releasing it from REV3 in the Pol ζ complex. Finally, p31comet, like TRIP13, is overexpressed in many cancers and this correlates with poor prognosis. Thus, we reveal a key player in the regulation of HR and TLS with significant clinical implications | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Fanconi anemia | |
| 650 | 4 | |a PARP inhibitor | |
| 650 | 4 | |a REV7 | |
| 650 | 4 | |a homologous recombination | |
| 650 | 4 | |a translesion synthesis | |
| 650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
| 650 | 7 | |a Cell Cycle Proteins |2 NLM | |
| 650 | 7 | |a MAD2L1 protein, human |2 NLM | |
| 650 | 7 | |a MAD2L1BP protein, human |2 NLM | |
| 650 | 7 | |a MAD2L2 protein, human |2 NLM | |
| 650 | 7 | |a Mad2 Proteins |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a ATPases Associated with Diverse Cellular Activities |2 NLM | |
| 650 | 7 | |a EC 3.6.4.- |2 NLM | |
| 650 | 7 | |a TRIP13 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.6.4.- |2 NLM | |
| 700 | 1 | |a Clairmont, Connor S |e verfasserin |4 aut | |
| 700 | 1 | |a Galli, Lucas D |e verfasserin |4 aut | |
| 700 | 1 | |a Moreau, Lisa A |e verfasserin |4 aut | |
| 700 | 1 | |a D'Andrea, Alan D |e verfasserin |4 aut | |
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