TRIP13 UniProt Q15645

1 alternative isoform · canonical 432 aa · microtubule organizing center; chromosome; nucleus; cytosol

TRIP13 is a hexameric AAA+ ATPase that functions as a universal remodeler of HORMA-domain proteins, coupling ATP-driven translocation to conformational conversion of its clients from a signaling-active 'closed' state to an inactive 'open' state [PMID:25918846, PMID:29973720]. Working with the adapter p31(comet), TRIP13 engages the disordered N-terminus of closed-conformation MAD2 through its axial pore loops and locally unfolds the MAD2 C-terminal αA helix, dissociating MAD2 from its partners; this remodeling disassembles the mitotic checkpoint complex and silences the spindle assembly checkpoint to permit anaphase onset, a reaction reconstituted from purified components and visualized by crystal and cryo-EM structures of the remodeling complex [PMID:25918846, PMID:25092294, PMID:29208896, PMID:29973720]. The same N-terminal engagement mechanism is conserved across HORMA clients: TRIP13 removes meiotic HORMAD1/HORMAD2 from synapsed chromosome axes and is required for synaptonemal complex formation, recombination progression after strand invasion, and crossover control during mouse meiosis [PMID:19851446, PMID:17696610, PMID:20711356, PMID:28659378, PMID:39207914]. Beyond mitosis and meiosis, TRIP13 disassembles the REV7(MAD2L2)-Shieldin and REV7-REV3/Pol-ζ complexes by the analogous closed-to-open conversion of REV7, shifting DNA repair toward homologous recombination and away from error-prone end-joining and translesion synthesis [PMID:31915374, PMID:33597306]. Its catalytic activity additionally supports HR-mediated tolerance of oncogene-induced replication stress in KRAS-mutant cells [PMID:40115747]. Biallelic loss-of-function TRIP13 mutations impair the spindle assembly checkpoint and cause chromosome missegregation in patient cells, with rescue upon TRIP13 reintroduction [PMID:28553959]. In cancer contexts, TRIP13 acts through additional partners—enhancing USP7-substrate deubiquitination to stabilize oncoproteins [PMID:34061780], and stabilizing or activating partners including HAT1, DDX21, ACTN4, and YWHAE to drive proliferative signaling [PMID:31533816, PMID:41535263, PMID:39187490, PMID:38012658]; it is also subject to EGFR-mediated Y56 phosphorylation that enhances NHEJ and radioresistance [PMID:34111559].