p31 <sup>comet</sup> promotes homologous recombination by inactivating REV7 through the TRIP13 ATPase
Prabha Sarangi, Connor S. Clairmont, Lucas D. Galli, Lisa A. Moreau, Alan D. D’Andrea
Abstract
Significance HORMA domain proteins play integral roles in several cellular processes such as mitosis, meiosis, and DNA repair. Intriguingly, despite their disparate cellular functions, the HORMA proteins MAD2, REV7, and HORMAD1/2 are controlled by a common regulatory circuit involving the ATPase TRIP13. Here, we extend this paradigm, showing that the adaptor protein p31 comet , known to mediate TRIP13 activity toward MAD2, is also involved in REV7 regulation. Notably, TRIP13 is overexpressed in many cancers, and TRIP13 hyperactivity inactivates the REV7-Shieldin complex, a critical determinant of sensitivity to Poly-ADP-ribose polymerase (PARP) inhibitors, causing resistance to this clinically important class of drugs. In this work, we present evidence that p31 comet overexpression is also common in cancer and largely mirrors the effects of TRIP13 overexpression.