Departamento de Genética, Universidad de Sevilla, Sevilla, 41080, Spain; Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla, 41092, Spain.
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla, 41092, Spain.
DNA Repair (Amst). 2018 Jun-Jul;66-67:11-23. doi: 10.1016/j.dnarep.2018.04.003. Epub 2018 Apr 22.
The appropriate repair of DNA double strand breaks is critical for genome maintenance. Thus, several cellular pathways collaborate to orchestrate a coordinated response. These include the repair of the breaks, which could be achieved by different mechanisms. A key protein involved in the regulation of the repair of broken chromosomes is CtIP. Here, we have found new partners of CtIP involved in the regulation of DNA break repair through affecting DNA end resection. We focus on the splicing complex SF3B and show that its depletion impairs DNA end resection and hampers homologous recombination. Functionally, SF3B controls CtIP function at, as least, two levels: by affecting CtIP mRNA levels and controlling CtIP recruitment to DNA breaks, in a way that requires ATM-mediated phosphorylation of SF3B2 at serine 289. Indeed, overexpression of CtIP rescues the resection defect caused by SF3B downregulation. Strikingly, other SF3B depletion phenotypes, such as impaired homologous recombination or cellular sensitivity to DNA damaging agents, are independent of CtIP levels, suggesting a more general role of SF3B in controlling the response to chromosome breaks.
DNA 双链断裂的适当修复对于基因组的维持至关重要。因此，几种细胞途径协同合作，以协调响应。这些途径包括通过不同的机制修复断裂。在调节断裂修复中涉及的一个关键蛋白是 CtIP。在这里，我们通过影响 DNA 末端切除发现了 CtIP 参与调节 DNA 断裂修复的新伴侣。我们专注于剪接复合物 SF3B，并表明其耗竭会损害 DNA 末端切除并阻碍同源重组。在功能上，SF3B 通过至少两个水平控制 CtIP 的功能：通过影响 CtIP mRNA 水平和控制 CtIP 募集到 DNA 断裂，以需要 ATM 介导的 SF3B2 丝氨酸 289 磷酸化的方式。实际上，CtIP 的过表达可挽救由 SF3B 下调引起的切除缺陷。引人注目的是，其他 SF3B 耗竭表型，如同源重组受损或细胞对 DNA 损伤剂的敏感性，与 CtIP 水平无关，这表明 SF3B 在控制对染色体断裂的响应方面具有更普遍的作用。
