蛋白质复合物凝聚素通过维持姊妹染色单体的连锁及通过DNA环外推形式折叠染色质以调节更高级别的染色体构架。受损的凝聚素功能是一组异质性的遗传综合征的基础，并与癌症相关。在这里，我们绘制了对凝聚素调控因子DDX11和ESCO2缺陷的人类细胞系的遗传依赖性图谱。所得到的合成致死网络在参与DNA复制和有丝分裂的基因中富集，并支持存在着姊妹染色体连锁建立的平行途径。在这些研究中，我们确定了染色质结合的含有BRCT结构域的PAXIP1蛋白作为一个新的凝聚素调控因子。PAXIP1的耗竭严重加重了ESCO2突变细胞的连锁缺陷，导致有丝分裂细胞死亡。PAXIP1促进全局染色质凝聚素的结合，独立于DNA复制，这个功能不能通过PAXIP1对转录或DNA修复的间接影响来解释。PAXIP1的凝聚素调控需要与其结合伴侣PAGR1及PAGR1中的保守的FDF结构域。PAXIP1与凝聚素共定位于多个基因组位点，包括活跃的基因启动子和增强子。可能，PAXIP1-PAGR1在调控凝聚素在染色质上的占位上的新发现的作用也与PAXIP1在转录、免疫细胞成熟和DNA修复中的先前已知功能相关。（翻译为学术论文所需的精确简化中文）© 作者（们）2023。由牛津大学出版社代表核酸研究出版。

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.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.