2026-06-14T03:33:33Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/132722024-11-29T16:03:16Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Morales, Carmen
author
Ruiz-Torres, Miguel
author
Rodríguez-Acebes, Sara
author
Rodríguez-Corsino, Miriam
author
Cisneros, David A
author
Peters, Jan-Michael
author
Lafarga, Vanesa
author
Megias Vazquez, Diego
author
Mendez, Juan
author
Losada, Ana
funder
Ministerio de Economía, Industria y Competitividad (España)
funder
Unión Europea. Comisión Europea
2021-08-06T11:59:42Z
2021-08-06T11:59:42Z
2020-01-03
J Biol Chem. 2020;295(1):146-157.
10.1074/jbc.RA119.011099
1083-351X
The Journal of biological chemistry
31757807
http://hdl.handle.net/20.500.12105/13272
Cohesin is a chromatin-bound complex that mediates sister chromatid cohesion and facilitates long-range interactions through DNA looping. How the transcription and replication machineries deal with the presence of cohesin on chromatin remains unclear. The dynamic association of cohesin with chromatin depends on WAPL cohesin release factor (WAPL) and on PDS5 cohesin-associated factor (PDS5), which exists in two versions in vertebrate cells, PDS5A and PDS5B. Using genetic deletion in mouse embryo fibroblasts and a combination of CRISPR-mediated gene editing and RNAi-mediated gene silencing in human cells, here we analyzed the consequences of PDS5 depletion for DNA replication. We found that either PDS5A or PDS5B is sufficient for proper cohesin dynamics and that their simultaneous removal increases cohesin's residence time on chromatin and slows down DNA replication. A similar phenotype was observed in WAPL-depleted cells. Cohesin down-regulation restored normal replication fork rates in PDS5-deficient cells, suggesting that chromatin-bound cohesin hinders the advance of the replisome. We further show that PDS5 proteins are required to recruit WRN helicase-interacting protein 1 (WRNIP1), RAD51 recombinase (RAD51), and BRCA2 DNA repair associated (BRCA2) to stalled forks and that in their absence, nascent DNA strands at unprotected forks are degraded by MRE11 homolog double-strand break repair nuclease (MRE11). These findings indicate that PDS5 proteins participate in replication fork protection and also provide insights into how cohesin and its regulators contribute to the response to replication stress, a common feature of cancer cells.
eng
PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.
journal article
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