Dataset Information

The FIGNL1-interacting protein C1orf112 is synthetic lethal with PICH and mediates RAD51 retention on chromatin

ABSTRACT: Joint DNA molecules are natural by-products of DNA replication and repair. Persistent joint molecules give rise to ultrafine DNA bridges (UFBs) in mitosis, which compromise sister chromatid separation. The DNA translocase PICH (ERCC6L) plays a central role in UFB resolution. To better understand the genetic context rendering cells dependent on PICH, a genome-wide loss-of-function screen was performed to identify the genetic contexts in which cells become dependent on PICH. In addition to genes involved in DNA cohesion, centromere stability and DNA damage repair, we identified the uncharacterized protein C1orf112. We find that C1orf112 interacts with and stabilizes the AAA+ ATPase FIGNL1. Inactivation of either C1orf112 or FIGNL1 resulted in UFB formation, prolonged retention of RAD51 on chromatin, impaired replication fork dynamics, and consequently impaired genome maintenance. Combined, our data reveal that inactivation of C1orf112 or FIGNL1 dysregulates RAD51 dynamics at replication forks, resulting in DNA replication defects, and a dependency on PICH to preserve cell viability.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Embryo, Embryonic Stem Cell, Kidney

DISEASE(S): Breast Cancer

SUBMITTER: Rolf de Boer

LAB HEAD: Marcel van Vugt

PROVIDER: PXD035876 | Pride | 2024-08-08

REPOSITORIES: Pride

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FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics.

Stok Colin C Tsaridou Stavroula S van den Tempel Nathalie N Everts Marieke M Wierenga Elles E Bakker Femke J FJ Kok Yannick Y Alves Inês Teles IT Jae Lucas T LT Raas Maximilian W D MWD Huis In 't Veld Pim J PJ de Boer H Rudolf HR Bhattacharya Arkajyoti A Karanika Eleftheria E Warner Harry H Chen Mengting M van de Kooij Bert B Dessapt Julien J Ter Morsche Lars L Perepelkina Polina P Fradet-Turcotte Amelie A Guryev Victor V Tromer Eelco C EC Chan Kok-Lung KL Fehrmann Rudolf S N RSN van Vugt Marcel A T M MATM

Cell reports 20230621 7

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 r ...[more]

PMID: 37347663

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Project description:During chromosome duplication the parental DNA molecule becomes over-wound, or positively supercoiled, in the region ahead of the advancing replication fork. To allow fork progression this superhelical tension has to be removed by topoisomerases, which operate by introducing transient DNA breaks. Positive supercoiling can also be diminished if the advancing fork rotates along the DNA helix, but then sister chromatid intertwinings form in its wake. Despite these insights it remains largely unknown how replicationinduced superhelical stress is dealt with on linear, eukaryotic chromosomes. Here we show that this stress increases with the length of budding yeast chromosomes. This opens for the possibility that superhelical tension is handled on a chromosome scale and not only within topologically closed chromosomal domains as the current view predicts. We found that inhibition of type I topoisomerases leads to a late replication delay of longer, but not shorter chromosomes. This phenotype is also displayed by cells expressing mutated versions of the cohesin- and condensin–related Smc5/6 complex. The chromosomal association of the Smc5/6 complex is shown to increase in response to chromosome lengthening, chromosome circularization, or inactivation of Topoisomerase 2, all having the potential to increase the number of sister chromatid intertwinings 3. Furthermore, non-functional Smc6 reduces the accumulation of intertwined sister plasmids after one round of replication in the absence of Topoisomerase 2 function. Our results demonstrate that the length of a chromosome influences the need of superhelical tension release in Saccharomyces cerevisiae, and allow us to propose a model where the Smc5/6 complex facilitates fork rotation by sequestering nascent chromatid intertwinings which form behind the replication machinery. Smc6、Nse4, and Scc2 profiles with or without topological tension was analyzed (in top2 mutant, cells with circular chromosome, and fragmented chromosome) . 17 ChIP samples and corresponding WCE fractions have been analyzed.

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