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 53B...

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Bibliographic Details
Published in:Nature cell biology Vol. 22; no. 1; pp. 87 - 96
Main Authors: Clairmont, Connor S, Sarangi, Prabha, Ponnienselvan, Karthikeyan, Galli, Lucas D, Csete, Isabelle, Moreau, Lisa, Adelmant, Guillaume, Chowdhury, Dipanjan, Marto, Jarrod A, D'Andrea, Alan D
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01.01.2020
Subjects:
Adenosine diphosphate
Adenosine triphosphatase
Anemia
ATPases Associated with Diverse Cellular Activities - drug effects
ATPases Associated with Diverse Cellular Activities - genetics
BRCA1 protein
BRCA1 Protein - deficiency
Breast cancer
Cell Cycle Proteins - drug effects
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Crosslinking
Deoxyribonucleic acid
Dismantling
DNA
DNA damage
DNA Damage - drug effects
DNA End-Joining Repair - genetics
DNA polymerase
DNA repair
DNA Repair - drug effects
DNA Repair - genetics
DNA Replication - drug effects
DNA Replication - genetics
DNA-directed DNA polymerase
Homology
Humans
Mad2 Proteins - genetics
Non-homologous end joining
Poly(ADP-ribose)
Poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Recombinational DNA Repair - genetics
Repair
Ribose
Telomere-Binding Proteins - drug effects
Telomere-Binding Proteins - genetics
ISSN:1465-7392, 1476-4679, 1476-4679
Online Access:Get full text
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Summary: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.
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ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/s41556-019-0442-y