Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, PO Box 1495, Spokane, WA 99210, USA.
Nucleic Acids Res. 2018 May 4;46(8):3981-3992. doi: 10.1093/nar/gky114.
Coats plus syndrome is a complex genetic disorder that can be caused by mutations in genes encoding the CTC1-STN1-TEN1 (CST) complex, a conserved single-stranded DNA binding protein complex. Studies have demonstrated that mutations identified in Coats plus patients are defective in telomere maintenance, and concluded that Coats plus may be caused by telomere dysfunction. Recent studies have established that CST also plays an important role in countering replication stress and protecting the stability of genomic fragile sites. However, it is unclear whether instabilities at genomic regions may promote Coats plus development. Here, we characterize eleven reported disease-causing CTC1 missense and small deletion mutations in maintaining genome stability. Our results show that these mutations induce spontaneous chromosome breakage and severe chromosome fragmentation that are further elevated by replication stress, leading to global genome instabilities. These mutations abolish or reduce CST interaction with RAD51, disrupt RAD51 foci formation, and/or diminish binding to GC-rich genomic fragile sites under replication stress. Furthermore, CTC1 mutations limit cell proliferation under unstressed condition and significantly reduce clonal viability under replication stress. Results also suggest that the aa 600-989 region of CTC1 contains a RAD51-interacting domain. Our findings thus provide molecular evidence linking replication-associated genomic defects with CP disease pathology.
coats 综合征是一种复杂的遗传疾病，可由编码 CTC1-STN1-TEN1（CST）复合物的基因突变引起，CST 复合物是一种保守的单链 DNA 结合蛋白复合物。研究表明，在 coats 综合征患者中发现的突变在端粒维持方面存在缺陷，并得出结论认为 coats 综合征可能是由于端粒功能障碍引起的。最近的研究已经证实 CST 还在应对复制应激和保护基因组脆弱位点稳定性方面发挥着重要作用。然而，基因组区域的不稳定性是否会促进 coats 综合征的发展尚不清楚。在这里，我们对 11 种已报道的导致疾病的 CTC1 错义突变和小缺失突变在维持基因组稳定性方面进行了特征描述。我们的结果表明，这些突变诱导自发的染色体断裂和严重的染色体碎片化，进一步被复制应激所加剧，导致全基因组不稳定性。这些突变会使 CST 与 RAD51 的相互作用丧失或减少，破坏 RAD51 焦点的形成，并/或在复制应激下减少与富含 GC 的基因组脆弱位点的结合。此外，CTC1 突变会在未受应激的条件下限制细胞增殖，并在复制应激下显著降低克隆存活能力。结果还表明，CTC1 的 aa600-989 区域含有一个与 RAD51 相互作用的结构域。因此，我们的研究结果提供了分子证据，将与复制相关的基因组缺陷与 CP 疾病病理联系起来。
