Journal
NATURE CELL BIOLOGY
Volume 22, Issue 1, Pages 87-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-019-0442-y
Keywords
-
Categories
Funding
- Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant [SU2C-AACR-DT16-15]
- American Association for Cancer Research, the scientific partner of SU2C
- US National Institutes of Health [R37HL052725, P01HL048546, P01 CA203655, R01 CA215489]
- US Department of Defense [BM110181]
- Breast Cancer Research Foundation
- Fanconi Anemia Research Fund
- Ludwig Center at Harvard
- Smith Family Foundation
- Leukemia and Lymphoma Society [5440-16]
- Claudia Adams Barr Program in Innovative Basic Cancer Research
Ask authors/readers for more resources
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-alpha) 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available