Ddb1 controls genome stability and meiosis in fission yeast
Ddb1 controls genome stability and meiosis in fission yeast
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DOI：
10.1101/gad.329905
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发表时间：
2005-04-01
影响因子：
10.5
通讯作者：
Nielsen, O
中科院分区：
文献类型：
--
作者：
Holmberg, C;Fleck, O;Nielsen, O
人紫外线损伤的DNA结合蛋白Ddb1与涉及核苷酸切除修复（NER）的cullin 4泛素连接酶相关。这些复合物还含有信号体（CSN），但NER相关的泛素化靶点尚未确定。我们报告说，分裂酵母Ddb1，Cullin 4（Pcu4），和CSN亚基Csn1和Csn2的降解所需的核糖核苷酸还原酶（RNR）抑制剂蛋白Spd1。Ddb1缺陷细胞具有> 20倍的自发突变率增加。这部分依赖于易错跨损伤DNA聚合酶。Spd1缺失大大降低了突变率，表明RNR活性不足占观察到的突变的50%。上位性分析表明，Ddb1有助于避免突变和耐受DNA损伤的途径不同于NER。最后，我们发现Ddb1/Csn1/Cullin 4介导的Spd1降解在细胞分化为减数分裂时变得至关重要。这些结果表明，Ddb 1，沿着与Cullin 4和信号体，构成了一个主要的途径控制基因组的稳定性，修复，并通过RNR调节分化。
The human UV-damaged DNA-binding protein Ddb1 associates with cullin 4 ubiquitin ligases implicated in nucleotide excision repair (NER). These complexes also contain the signalosome (CSN), but NER-relevant ubiquitination targets have not yet been identified. We report that fission yeast Ddb1, Cullin 4 (Pcu4), and CSN subunits Csn1 and Csn2 are required for degradation of the ribonucleotide reductase (RNR) inhibitor protein Spd1. Ddb1-deficient cells have > 20-fold increased spontaneous mutation rate. This is partly dependent on the error-prone translesion DNA polymerases. Spd1 deletion substantially reduced the mutation rate, suggesting that insufficient RNR activity accounts for similar to 50% of observed mutations. Epistasis analysis indicated that Ddb1 contributed to mutation avoidance and tolerance to DNA damage in a pathway distinct from NER. Finally, we show that Ddb1/Csn1/Cullin 4-mediated Spd1 degradation becomes essential when cells differentiate into meiosis. These results suggest that Ddb1, along with Cullin 4 and the signalosome, constitute a major pathway controlling genome stability, repair, and differentiation via RNR regulation.