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.
Original language | English |
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Article number | 112668 |
Pages (from-to) | 1-27 |
Number of pages | 27 |
Journal | Cell Reports |
Volume | 42 |
Issue number | 7 |
DOIs | |
Publication status | Published - 25 Jul 2023 |
Bibliographical note
Publisher Copyright:© 2023 The Author(s)
Funding
This work was supported by a European Research Council grant (ERC-Consolidator 681572 to M.A.T.M.v.V.). We thank Thijn Brummelkamp, Maarten Hekkelmans, and Steven Bergink for technical support; Audrey Anastasia for figure design; and David Cortez for sharing reagents. We thank Amélie Fradet-Turcotte and Alexandre Ortwein for discussing unpublished work.
Funders | Funder number |
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European Research Council | ERC-Consolidator 681572 |
Keywords
- Adenosine Triphosphatases/metabolism
- Chromatids/metabolism
- DNA
- DNA Damage
- DNA Replication/genetics
- Mitosis
- Proteins/genetics
- Rad51 Recombinase/genetics