FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics
Colin Stok, Stavroula Tsaridou, Nathalie van den Tempel, Marieke Everts, Elles Wierenga, Femke J. Bakker, Yannick P. Kok, Inês Teles Alves, Lucas T. Jae, Maximilian W.D. Raas, Pim J. Huis in ’t Veld, H. Rudolf de Boer, Arkajyoti Bhattacharya, Eleftheria Karanika, Harry Warner, Mengting Chen, Bert van de Kooij, Julien Dessapt, Lars ter Morsche, Polina A. Perepelkina, Amélie Fradet‐Turcotte, Victor Guryev, Eelco C. Tromer, Kok‐Lung Chan, Rudolf S.N. Fehrmann, Marcel A.T.M. van Vugt
Abstract
Joint DNA molecules are natural byproducts of DNA replication and repair. Persistent joint molecules give rise to ultrafine DNA bridges (UFBs) in mitosis, compromising sister chromatid separation. The DNA translocase PICH ( ERCC6L ) has a central role in UFB resolution. A genome-wide loss-of-function screen is performed to identify the genetic context of PICH dependency. In addition to genes involved in DNA condensation, centromere stability, and DNA-damage repair, we identify FIGNL1-interacting regulator of recombination and mitosis (FIRRM), formerly known as C1orf112. We find that FIRRM interacts with and stabilizes the AAA + ATPase FIGNL1. Inactivation of either FIRRM or FIGNL1 results in UFB formation, prolonged accumulation of RAD51 at nuclear foci, and impaired replication fork dynamics and consequently impairs genome maintenance. Combined, our data suggest that inactivation of FIRRM and FIGNL1 dysregulates RAD51 dynamics at replication forks, resulting in persistent DNA lesions and a dependency on PICH to preserve cell viability.