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eSymposia | Genomic Stability and DNA Repair


TRIP13-p31 is a negative regulator of the multifunctional REV7 protein


Sep 21, 2020 12:00am ‐ Sep 21, 2020 12:00am

Description

TRIP13-p31 is a negative regulator of the multifunctional REV7 protein Connor S. Clairmont*1, Prabha Sarangi*1, Lucas D. Galli1, Lisa A. Moreau1, Alan D. D’Andrea1,2 1. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA 2. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, 02215, USA *These authors contributed equally to this work The REV7-Shieldin complex is an important component of the cellular machinery that controls DNA double strand break (DSB) repair. REV7-Shieldin is recruited to DSBs downstream of 53BP1 and counteracts DNA end resection, a prerequisite for repair by homologous recombination (HR). REV7 is a HORMA domain protein that mediates the critical interaction between SHLD3 and SHLD2. Similar to other HORMA domain proteins, REV7 binds to its partners through the closing of its “seatbelt” domain, resulting in extremely stable interactions. TRIP13 is a AAA+ ATPase that actively “opens” the seatbelt of REV7 and other HORMA domain proteins, thereby dissociating the involved complexes. As such, TRIP13 is an important regulator of HR activity - by dissociating the REV7-Shieldin complex, it promotes end resection and HR. Here we identify the small HORMA-like protein, p31comet as a critical adapter of the REV7-TRIP13 interaction. p31-deficient cells exhibit hyperactivation of the REV7-Shieldin complex, resulting in HR deficiency and hypersensitivity to poly-ADP ribose polymerase (PARP) inhibition. Conversely, overexpression of p31 leads to increased HR utilization, even in the otherwise HR-deficient context of BRCA1-knockout cells. Furthermore, p31 overexpression is frequently observed in cancers and correlates with prognosis and genomic mutation signatures, suggesting that it may be a determinant of mutagenesis and drug response in cancer.

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