TRIP13 regulates DNA repair pathway choice through REV7 conformational change
DNA double-strand breaks (DSBs) are repaired through homology-directed repair (HDR) or non-homologous end joining (NHEJ). BRCA1/2-deficient cancer cells cannot perform HDR, conferring sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). However, concomitant loss of the pro-NHEJ factors 53BP1, RIF1, REV7-Shieldin (SHLD1-3) or CST-DNA polymerase alpha (Pol-α) in BRCA1-deficient cells restores HDR and PARPi resistance. Here, we identify the TRIP13 ATPase as a negative regulator of REV7. We show that REV7 exists in active 'closed' and inactive 'open' conformations, and TRIP13 catalyses the inactivating conformational change, thereby dissociating REV7-Shieldin to promote HDR. TRIP13 similarly disassembles the REV7-REV3 translesion synthesis (TLS) complex, a component of the Fanconi anaemia pathway, inhibiting error-prone replicative lesion bypass and interstrand crosslink repair. Importantly, TRIP13 overexpression is common in BRCA1-deficient cancers, confers PARPi resistance and correlates with poor prognosis. Thus, TRIP13 emerges as an important regulator of DNA repair pathway choice-promoting HDR, while suppressing NHEJ and TLS.
| Errataetall: |
CommentIn: Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):27761-27763. - PMID 33122436 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
|---|---|
| Enthalten in: |
Nature cell biology - 22(2020), 1 vom: 27. Jan., Seite 87-96 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Clairmont, Connor S [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 23.04.2020 Date Revised 11.02.2024 published: Print-Electronic CommentIn: Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):27761-27763. - PMID 33122436 Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41556-019-0442-y |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM305147110 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM305147110 | ||
| 003 | DE-627 | ||
| 005 | 20240211231825.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41556-019-0442-y |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1288.xml |
| 035 | |a (DE-627)NLM305147110 | ||
| 035 | |a (NLM)31915374 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Clairmont, Connor S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a TRIP13 regulates DNA repair pathway choice through REV7 conformational change |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.04.2020 | ||
| 500 | |a Date Revised 11.02.2024 | ||
| 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 DNA double-strand breaks (DSBs) are repaired through homology-directed repair (HDR) or non-homologous end joining (NHEJ). BRCA1/2-deficient cancer cells cannot perform HDR, conferring sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). However, concomitant loss of the pro-NHEJ factors 53BP1, RIF1, REV7-Shieldin (SHLD1-3) or CST-DNA polymerase alpha (Pol-α) in BRCA1-deficient cells restores HDR and PARPi resistance. Here, we identify the TRIP13 ATPase as a negative regulator of REV7. We show that REV7 exists in active 'closed' and inactive 'open' conformations, and TRIP13 catalyses the inactivating conformational change, thereby dissociating REV7-Shieldin to promote HDR. TRIP13 similarly disassembles the REV7-REV3 translesion synthesis (TLS) complex, a component of the Fanconi anaemia pathway, inhibiting error-prone replicative lesion bypass and interstrand crosslink repair. Importantly, TRIP13 overexpression is common in BRCA1-deficient cancers, confers PARPi resistance and correlates with poor prognosis. Thus, TRIP13 emerges as an important regulator of DNA repair pathway choice-promoting HDR, while suppressing NHEJ and TLS | ||
| 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 | 7 | |a BRCA1 Protein |2 NLM | |
| 650 | 7 | |a BRCA1 protein, human |2 NLM | |
| 650 | 7 | |a Cell Cycle Proteins |2 NLM | |
| 650 | 7 | |a Mad2 Proteins |2 NLM | |
| 650 | 7 | |a Poly(ADP-ribose) Polymerase Inhibitors |2 NLM | |
| 650 | 7 | |a Telomere-Binding 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 Sarangi, Prabha |e verfasserin |4 aut | |
| 700 | 1 | |a Ponnienselvan, Karthikeyan |e verfasserin |4 aut | |
| 700 | 1 | |a Galli, Lucas D |e verfasserin |4 aut | |
| 700 | 1 | |a Csete, Isabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Moreau, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Adelmant, Guillaume |e verfasserin |4 aut | |
| 700 | 1 | |a Chowdhury, Dipanjan |e verfasserin |4 aut | |
| 700 | 1 | |a Marto, Jarrod A |e verfasserin |4 aut | |
| 700 | 1 | |a D'Andrea, Alan D |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature cell biology |d 1999 |g 22(2020), 1 vom: 27. Jan., Seite 87-96 |w (DE-627)NLM104898879 |x 1476-4679 |7 nnns |
| 773 | 1 | 8 | |g volume:22 |g year:2020 |g number:1 |g day:27 |g month:01 |g pages:87-96 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41556-019-0442-y |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 22 |j 2020 |e 1 |b 27 |c 01 |h 87-96 | ||