Nature cell biology, 2020-01, Vol.22 (1), p.87
2020
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- Autor(en) / Beteiligte
- Titel
- TRIP13 regulates DNA repair pathway choice through REV7 conformational change
- Ist Teil von
- Nature cell biology, 2020-01, Vol.22 (1), p.87
- Ort / Verlag
- England
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- eISSN: 1476-4679DOI: 10.1038/s41556-019-0442-yTitel-ID: cdi_pubmed_primary_31915374
- Format
- –
- Schlagworte
- ATPases Associated with Diverse Cellular Activities - drug effects, ATPases Associated with Diverse Cellular Activities - genetics, BRCA1 Protein - deficiency, Cell Cycle Proteins - drug effects, Cell Cycle Proteins - genetics, Cell Cycle Proteins - metabolism, DNA Damage - drug effects, DNA End-Joining Repair - genetics, DNA Repair - drug effects, DNA Repair - genetics, DNA Replication - drug effects, DNA Replication - genetics, Humans, Mad2 Proteins - genetics, Poly(ADP-ribose) Polymerase Inhibitors - pharmacology, Recombinational DNA Repair - genetics, Telomere-Binding Proteins - drug effects, Telomere-Binding Proteins - genetics