Cell Reports (Jul 2023)
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 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 Perepelkina,
- Amelie Fradet-Turcotte,
- Victor Guryev,
- Eelco C. Tromer,
- Kok-Lung Chan,
- Rudolf S.N. Fehrmann,
- Marcel A.T.M. van Vugt
Affiliations
- Colin Stok
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Stavroula Tsaridou
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Nathalie van den Tempel
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Marieke Everts
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Elles Wierenga
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Femke J. Bakker
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Yannick Kok
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Inês Teles Alves
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Lucas T. Jae
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377 Munich, Germany
- Maximilian W.D. Raas
- Oncode Institute, Hubrecht Institute, Royal Academy of Arts and Sciences, Uppsalalaan 8, 3584CT Utrecht, the Netherlands; Theoretical Biology and Bioinformatics, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands
- Pim J. Huis in 't Veld
- Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany
- H. Rudolf de Boer
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Arkajyoti Bhattacharya
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Eleftheria Karanika
- Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK
- Harry Warner
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Mengting Chen
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Bert van de Kooij
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Julien Dessapt
- CHU de Québec Research Center-Université Laval (L'Hôtel-Dieu de Québec), Cancer Research Center, Université Laval, Québec, QC GIR 3S3, Canada
- Lars ter Morsche
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Polina Perepelkina
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Amelie Fradet-Turcotte
- CHU de Québec Research Center-Université Laval (L'Hôtel-Dieu de Québec), Cancer Research Center, Université Laval, Québec, QC GIR 3S3, Canada
- Victor Guryev
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Eelco C. Tromer
- Cell Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, Faculty of Science and Engineering, University of Groningen, Nijenborgh 7, 9747 AG Groningen, the Netherlands
- Kok-Lung Chan
- Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK
- Rudolf S.N. Fehrmann
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Marcel A.T.M. van Vugt
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 7
p. 112668
Abstract
Summary: 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.
