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

doi:10.1016/j.celrep.2023.112668

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 PerepelkinaAmelie Fradet-Turcotte, Victor Guryev, Eelco C Tromer, Kok-Lung Chan, Rudolf S N Fehrmann, Marcel A T M van Vugt^*

^*Corresponding author voor dit werk

Onderzoeksoutput › Academic › peer review

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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.

Originele taal-2	English
Artikelnummer	112668
Aantal pagina's	27
Tijdschrift	Cell reports
Volume	42
Nummer van het tijdschrift	7
Vroegere onlinedatum	21-jun.-2023
DOI's	https://doi.org/10.1016/j.celrep.2023.112668
Status	Published - 25-jul.-2023

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Stok, C., Tsaridou, S., van den Tempel, N., Everts, M., Wierenga, E., Bakker, F. J., Kok, Y., Alves, I. T., Jae, L. T., Raas, M. W. D., Huis In 't Veld, P. J., de Boer, H. R., Bhattacharya, A., Karanika, E., Warner, H., Chen, M., van de Kooij, B., Dessapt, J., ter Morsche, L., ... van Vugt, M. A. T. M. (2023). FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics. Cell reports, 42(7), Artikel 112668. https://doi.org/10.1016/j.celrep.2023.112668

@article{677fd494da0a49e99a0f6f7f29895d50,

title = "FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics",

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. ",

author = "Colin Stok and Stavroula Tsaridou and {van den Tempel}, Nathalie and Marieke Everts and Elles Wierenga and Bakker, {Femke J} and Yannick Kok and Alves, {In{\^e}s Teles} and Jae, {Lucas T} and Raas, {Maximilian W D} and {Huis In 't Veld}, {Pim J} and {de Boer}, {H Rudolf} and Arkajyoti Bhattacharya and Eleftheria Karanika and Harry Warner and Mengting Chen and {van de Kooij}, Bert and Julien Dessapt and {ter Morsche}, Lars and Polina Perepelkina and Amelie Fradet-Turcotte and Victor Guryev and Tromer, {Eelco C} and Kok-Lung Chan and Fehrmann, {Rudolf S N} and {van Vugt}, {Marcel A T M}",

year = "2023",

month = jul,

day = "25",

doi = "10.1016/j.celrep.2023.112668",

language = "English",

volume = "42",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "7",

}

Stok, C, Tsaridou, S, van den Tempel, N, Everts, M, Wierenga, E, Bakker, FJ, Kok, Y, Alves, IT, Jae, LT, Raas, MWD, Huis In 't Veld, PJ, de Boer, HR , Bhattacharya, A, Karanika, E, Warner, H , Chen, M , van de Kooij, B, Dessapt, J, ter Morsche, L, Perepelkina, P, Fradet-Turcotte, A, Guryev, V , Tromer, EC, Chan, K-L, Fehrmann, RSN & van Vugt, MATM 2023, 'FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics', Cell reports, vol. 42, nr. 7, 112668. https://doi.org/10.1016/j.celrep.2023.112668

TY - JOUR

T1 - FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics

AU - Stok, Colin

AU - Tsaridou, Stavroula

AU - van den Tempel, Nathalie

AU - Everts, Marieke

AU - Wierenga, Elles

AU - Bakker, Femke J

AU - Kok, Yannick

AU - Alves, Inês Teles

AU - Jae, Lucas T

AU - Raas, Maximilian W D

AU - Huis In 't Veld, Pim J

AU - de Boer, H Rudolf

AU - Bhattacharya, Arkajyoti

AU - Karanika, Eleftheria

AU - Warner, Harry

AU - Chen, Mengting

AU - van de Kooij, Bert

AU - Dessapt, Julien

AU - ter Morsche, Lars

AU - Perepelkina, Polina

AU - Fradet-Turcotte, Amelie

AU - Guryev, Victor

AU - Tromer, Eelco C

AU - Chan, Kok-Lung

AU - Fehrmann, Rudolf S N

AU - van Vugt, Marcel A T M

PY - 2023/7/25

Y1 - 2023/7/25

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2023.112668

DO - 10.1016/j.celrep.2023.112668

M3 - Article

C2 - 37347663

SN - 2211-1247

VL - 42

JO - Cell reports

JF - Cell reports

IS - 7

M1 - 112668

ER -

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

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