TRIP13 regulates DNA repair pathway choice through REV7 conformational change

Nat Cell Biol. 2020 Jan;22(1):87-96. doi: 10.1038/s41556-019-0442-y. Epub 2020 Jan 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • BRCA1 Protein
  • BRCA1 protein, human
  • Cell Cycle Proteins
  • Mad2 Proteins
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Telomere-Binding Proteins
  • ATPases Associated with Diverse Cellular Activities
  • TRIP13 protein, human