van Schie Janne J M, de Lint Klaas, Molenaar Thom M, Moronta Gines Macarena, Balk Jesper A, Rooimans Martin A, Roohollahi Khashayar, Pai Govind M, Borghuis Lauri, Ramadhin Anisha R, Corazza Francesco, Dorsman Josephine C, Wendt Kerstin S, Wolthuis Rob M F, de Lange Job
Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Human Genetics, Section Oncogenetics, Amsterdam, The Netherlands.
Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands.
Nucleic Acids Res. 2023 Oct 13;51(18):9594-9609. doi: 10.1093/nar/gkad756.
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.
黏连蛋白复合体通过维持姐妹染色单体黏连以及通过DNA环挤压折叠染色质来调节高阶染色体结构。黏连蛋白功能受损是一组异质性遗传综合征的基础，并与癌症相关。在这里，我们绘制了黏连调节因子DDX11和ESCO2缺陷的人类细胞系的遗传依赖性图谱。所获得的合成致死网络强烈富集了参与DNA复制和有丝分裂的基因，并支持平行姐妹染色单体黏连建立途径的存在。在这些命中基因中，我们鉴定出染色质结合的含BRCT结构域的蛋白PAXIP1作为一种新的黏连蛋白调节因子。PAXIP1的缺失严重加剧了ESCO2突变细胞中的黏连缺陷，导致有丝分裂细胞死亡。PAXIP1促进黏连蛋白与整体染色质的结合，独立于DNA复制，这一功能无法用PAXIP1对转录或DNA修复的间接作用来解释。PAXIP1对黏连蛋白的调节需要其结合伴侣PAGR1以及PAGR1中一个保守的FDF基序。PAXIP1与黏连蛋白在多个基因组位点共定位，包括活性基因启动子和增强子。可能，PAXIP1-PAGR1在调节染色质上黏连蛋白占据方面的这一新发现的作用也与PAXIP1先前在转录、免疫细胞成熟和DNA修复中的功能相关。
Zotero 插件
