Sundaramoorthy Sriramkumar, Vázquez-Novelle María Dolores, Lekomtsev Sergey, Howell Michael, Petronczki Mark
Cell Division and Aneuploidy Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms Hertfordshire, UK.
High-throughput Screening Laboratory, Cancer Research UK London Research Institute, London, UK.
EMBO J. 2014 Nov 18;33(22):2623-42. doi: 10.15252/embj.201488244. Epub 2014 Sep 25.
Sister chromatid cohesion mediated by the cohesin complex is essential for chromosome segregation during cell division. Using functional genomic screening, we identify a set of 26 pre-mRNA splicing factors that are required for sister chromatid cohesion in human cells. Loss of spliceosome subunits increases the dissociation rate of cohesin from chromatin and abrogates cohesion after DNA replication, ultimately causing mitotic catastrophe. Depletion of splicing factors causes defective processing of the pre-mRNA encoding sororin, a factor required for the stable association of cohesin with chromatin, and an associated reduction of sororin protein level. Expression of an intronless version of sororin and depletion of the cohesin release protein WAPL suppress the cohesion defect in cells lacking splicing factors. We propose that spliceosome components contribute to sister chromatid cohesion and mitotic chromosome segregation through splicing of sororin pre-mRNA. Our results highlight the loss of cohesion as an early cellular consequence of compromised splicing. This may have clinical implications because SF3B1, a splicing factor that we identify to be essential for cohesion, is recurrently mutated in chronic lymphocytic leukaemia.
由黏连蛋白复合体介导的姐妹染色单体黏连对于细胞分裂过程中的染色体分离至关重要。通过功能基因组筛选，我们鉴定出一组26种前体mRNA剪接因子，它们是人类细胞中姐妹染色单体黏连所必需的。剪接体亚基的缺失会增加黏连蛋白从染色质上的解离速率，并在DNA复制后消除黏连，最终导致有丝分裂灾难。剪接因子的耗竭会导致编码sororin的前体mRNA加工缺陷，sororin是黏连蛋白与染色质稳定结合所需的一个因子，同时会使sororin蛋白水平相应降低。无内含子版本的sororin的表达以及黏连蛋白释放蛋白WAPL的耗竭可抑制缺乏剪接因子的细胞中的黏连缺陷。我们提出，剪接体成分通过sororin前体mRNA的剪接作用促进姐妹染色单体黏连和有丝分裂染色体分离。我们的结果突出了黏连丧失作为剪接受损的早期细胞后果。这可能具有临床意义，因为我们鉴定出的对黏连至关重要的剪接因子SF3B1在慢性淋巴细胞白血病中经常发生突变。
