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首页> 外文期刊>Genome Integrity >Differential genetic interactions between Sgs1, DNA-damage checkpoint components and DNA repair factors in the maintenance of chromosome stability
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Differential genetic interactions between Sgs1, DNA-damage checkpoint components and DNA repair factors in the maintenance of chromosome stability

机译：Sgs1，DNA损伤检查点成分和DNA修复因子之间的差异遗传相互作用在维持染色体稳定性中的作用

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Background Genome instability is associated with human cancers and chromosome breakage syndromes, including Bloom's syndrome, caused by inactivation of BLM helicase. Numerous mutations that lead to genome instability are known, yet how they interact genetically is poorly understood. Results We show that spontaneous translocations that arise by nonallelic homologous recombination in DNA-damage-checkpoint-defective yeast lacking the BLM-related Sgs1 helicase (sgs1Δ mec3Δ) are inhibited if cells lack Mec1/ATR kinase. Tel1/ATM, in contrast, acts as a suppressor independently of Mec3 and Sgs1. Translocations are also inhibited in cells lacking Dun1 kinase, but not in cells defective in a parallel checkpoint branch defined by Chk1 kinase. While we had previously shown that RAD51 deletion did not inhibit translocation formation, RAD59 deletion led to inhibition comparable to the rad52Δ mutation. A candidate screen of other DNA metabolic factors identified Exo1 as a strong suppressor of chromosomal rearrangements in the sgs1Δ mutant, becoming even more important for chromosomal stability upon MEC3 deletion. We determined that the C-terminal third of Exo1, harboring mismatch repair protein binding sites and phosphorylation sites, is dispensable for Exo1's roles in chromosomal rearrangement suppression, mutation avoidance and resistance to DNA-damaging agents. Conclusions Our findings suggest that translocations between related genes can form by Rad59-dependent, Rad51-independent homologous recombination, which is independently suppressed by Sgs1, Tel1, Mec3 and Exo1 but promoted by Dun1 and the telomerase-inhibitor Mec1. We propose a model for the functional interaction between mitotic recombination and the DNA-damage checkpoint in the suppression of chromosomal rearrangements in sgs1Δ cells.
机译：背景基因组不稳定性与人类癌症和BLM解旋酶失活引起的染色体断裂综合征（包括Bloom综合征）有关。导致基因组不稳定的许多突变是已知的，但人们对其遗传相互作用的了解却很少。结果我们显示，如果缺少细胞的Mec1 / ATR激酶，则在缺乏BLM相关Sgs1解旋酶的DNA损伤检查点缺陷型酵母中，非等位基因同源重组引起的自发易位受到抑制。相反，Tel1 / ATM则独立于Mec3和Sgs1充当抑制器。在缺乏Dun1激酶的细胞中也可抑制易位，但在由Chk1激酶定义的平行检查点分支中的缺陷细胞中则不会受到抑制。尽管我们先前已经证明RAD51缺失不会抑制易位形成，但RAD59缺失导致的抑制作用与rad52Δ突变相当。其他DNA代谢因子的候选筛选将Exo1鉴定为sgs1Δ突变体中染色体重排的强抑制剂，对删除MEC3后的染色体稳定性变得更加重要。我们确定，Exo1的C末端三分之一具有错配修复蛋白结合位点和磷酸化位点，对于Exo1在染色体重排抑制，避免突变和对DNA破坏剂的抵抗中的作用是可有可无的。结论我们的发现表明相关基因之间的易位可通过Rad59依赖性，Rad51无关的同源重组形成，该重组受Sgs1，Tel1，Mec3和Exo1独立抑制，但由Dun1和端粒酶抑制剂Mec1促进。我们提出了有丝分裂重组和DNA损伤检查点之间功能相互作用的模型，以抑制sgs1Δ细胞中的染色体重排。

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