TY - JOUR
T1 - CRISPR screens in sister chromatid cohesion defective cells reveal PAXIP1-PAGR1 as regulator of chromatin association of cohesin
AU - van Schie, Janne J.M.
AU - de Lint, Klaas
AU - Molenaar, Thom M.
AU - Gines, Macarena Moronta
AU - Balk, Jesper A.
AU - Rooimans, Martin A.
AU - Roohollahi, Khashayar
AU - Pai, Govind M.
AU - Borghuis, Lauri
AU - Ramadhin, Anisha R.
AU - Corazza, Francesco
AU - Dorsman, Josephine C.
AU - Wendt, Kerstin S.
AU - Wolthuis, Rob M.F.
AU - de Lange, Job
N1 - Funding Information: We thank Isabel Mayayo-Peralta, Stefan Prekovic and Wilbert Zwart for sharing unpublished work and for insightful discussions, the Amsterdam UMC Core Facility Genomics for sequencing, the ENCODE Consortium and the Bernstein (Broad) and Myers (HAIB) lab for generating ENCODE datasets, and Yiping He for sharing HCT116 KMT2D-KO cells. Dutch Cancer Society [KWF grants 10701 and 13645 to J.d.L.]. Funding for open access charge: Dedicated budget that is available within our own research group. Conflict of interest statement. None declared. Publisher Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2023/10/13
Y1 - 2023/10/13
N2 - The cohesin complex regulates higher order chromosome architecture through maintaining sister chromatid cohesion and folding chromatin by DNA loop extrusion. Impaired cohesin function underlies a heterogeneous group of genetic syndromes and is associated with cancer. Here, we mapped the genetic dependencies of human cell lines defective of cohesion regulators DDX11 and ESCO2. The obtained synthetic lethality networks are strongly enriched for genes involved in DNA replication and mitosis and support the existence of parallel sister chromatid cohesion establishment pathways. Among the hits, we identify the chromatin binding, BRCT-domain containing protein PAXIP1 as a novel cohesin regulator. Depletion of PAXIP1 severely aggravates cohesion defects in ESCO2 mutant cells, leading to mitotic cell death. PAXIP1 promotes global chromatin association of cohesin, independent of DNA replication, a function that cannot be explained by indirect effects of PAXIP1 on transcription or DNA repair. Cohesin regulation by PAXIP1 requires its binding partner PAGR1 and a conserved FDF motif in PAGR1. PAXIP1 co-localizes with cohesin on multiple genomic loci, including active gene promoters and enhancers. Possibly, this newly identified role of PAXIP1-PAGR1 in regulating cohesin occupancy on chromatin is also relevant for previously described functions of PAXIP1 in transcription, immune cell maturation and DNA repair.
AB - The cohesin complex regulates higher order chromosome architecture through maintaining sister chromatid cohesion and folding chromatin by DNA loop extrusion. Impaired cohesin function underlies a heterogeneous group of genetic syndromes and is associated with cancer. Here, we mapped the genetic dependencies of human cell lines defective of cohesion regulators DDX11 and ESCO2. The obtained synthetic lethality networks are strongly enriched for genes involved in DNA replication and mitosis and support the existence of parallel sister chromatid cohesion establishment pathways. Among the hits, we identify the chromatin binding, BRCT-domain containing protein PAXIP1 as a novel cohesin regulator. Depletion of PAXIP1 severely aggravates cohesion defects in ESCO2 mutant cells, leading to mitotic cell death. PAXIP1 promotes global chromatin association of cohesin, independent of DNA replication, a function that cannot be explained by indirect effects of PAXIP1 on transcription or DNA repair. Cohesin regulation by PAXIP1 requires its binding partner PAGR1 and a conserved FDF motif in PAGR1. PAXIP1 co-localizes with cohesin on multiple genomic loci, including active gene promoters and enhancers. Possibly, this newly identified role of PAXIP1-PAGR1 in regulating cohesin occupancy on chromatin is also relevant for previously described functions of PAXIP1 in transcription, immune cell maturation and DNA repair.
UR - http://www.scopus.com/inward/record.url?scp=85174919827&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/nar/gkad756
DO - https://doi.org/10.1093/nar/gkad756
M3 - Article
C2 - 37702151
SN - 0305-1048
VL - 51
SP - 9594
EP - 9609
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 18
ER -