P31comet and TRIP13 recycle Rev7 to regulate DNA repair

Abstract

Proteins of the HORMA domain family, named for its three founding members Hop1, Rev7, and Mad2, play key roles in a broad range of eukaryotic signaling pathways, from chromosome segregation and meiotic recombination, to DNA repair, to the initiation of autophagy (1). The HORMA domain nucleates assembly of multiprotein signaling complexes by wrapping its C-terminal “safety belt” region entirely around a short, 6- to 10-amino acid “closure motif” in a binding partner, resulting in a highly stable complex (Fig. 1 A ). While the mechanisms governing assembly of HORMA protein signaling complexes vary, many HORMA proteins share a common disassembly pathway involving two proteins, p31comet and the AAA+ ATPase TRIP13. p31comet, itself a diverged HORMA protein, specifically binds HORMA proteins in their “closed” partner-bound conformation, and recruits them to TRIP13 (2⇓–4). TRIP13 partially unfolds the HORMA domain, releasing the bound closure motif and converting the substrate HORMA protein to an inactive “open” conformation poised for rebinding (5⇓⇓⇓⇓–10). This HORMA recycling pathway was first described for the spindle assembly checkpoint protein Mad2 (11⇓–13), and has since been extended to include the meiotic recombination factor Hop1 and its relatives, collectively termed meiotic HORMADs (14⇓⇓⇓⇓⇓–20). A key question has been whether TRIP13 and p31comet regulate other HORMA protein families, including the DNA repair factor Rev7 and the autophagy regulators Atg13 and Atg101. In two recent manuscripts, Clairmont et al. (21) and Sarangi et al. (22) provide convincing evidence that TRIP13 and p31comet regulate Rev7 function in two DNA repair pathways, and that … [↵][1]1Email: kcorbett{at}ucsd.edu. [1]: #xref-corresp-1-1