Fission Yeast Hsk1 (Cdc7) Kinase Is Required After Replication Initiation for Induced Mutagenesis and Proper Response to DNA Alkylation Damage
Fission Yeast Hsk1 (Cdc7) Kinase Is Required After Replication Initiation for Induced Mutagenesis and Proper Response to DNA Alkylation Damage
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DOI：
10.1534/genetics.109.112284
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发表时间：
2010-05-01
期刊：
影响因子：
3.3
通讯作者：
Forsburg, Susan L.
中科院分区：
文献类型：
--
作者：
Dolan, William P.;Le, Anh-Huy;Forsburg, Susan L.
裂变酵母基因组的稳定需要保守的s期激酶Hsk1 （Cdc7）和它的伙伴Dfp1 （Dbf4）。除了它们在DNA复制起始中的既定功能外，我们发现这些蛋白质在S期和G2期后期维持基因组完整性方面也很重要。Hsk1细胞的有丝分裂重组率增加，需要重组蛋白才能存活。hsk1和dpf1突变体对烷基化损伤非常敏感，但在诱导诱变方面存在缺陷。Hsk1和Dfp1即使在S期之后也与染色质相关，并且对MMS损伤的正常反应与维持染色质上完整的Dfp1相关。对mms敏感突变体的筛选发现了一种新的截断等位基因rad35 (dfp1-(1-519))，以及其他损伤相关基因的等位基因。虽然Hsk1-Dfp1与Swi1-Swi3叉保护复合体一起起作用，但它也独立于FPC促进DNA修复。我们得出结论，Hsk1-Dfp1激酶在启动后发挥作用，维持复制叉的稳定性，这一活性可能由Dfp1的C端介导。
Genome stability in fission yeast requires the conserved S-phase kinase Hsk1 (Cdc7) and its partner Dfp1 (Dbf4). In addition to their established function in the initiation of DNA replication, we show that these proteins are important in maintaining genome integrity later in S phase and G2. hsk1 cells suffer increased rates of mitotic recombination and require recombination proteins for survival. Both hsk1 and dfp1 mutants are acutely sensitive to alkylation damage yet defective in induced mutagenesis. Hsk1 and Dfp1 are associated with the chromatin even after S phase, and normal response to MMS damage correlates with the maintenance of intact Dfp1 on chromatin. A screen for MMS-sensitive mutants identified a novel truncation allele, rad35 (dfp1-(1-519)), as well as alleles of other damage-associated genes. Although Hsk1-Dfp1 functions with the Swi1-Swi3 fork protection complex, it also acts independently of the FPC to promote DNA repair. We conclude that Hsk1-Dfp1 kinase functions post-initiation to maintain replication fork stability, an activity potentially mediated by the C terminus of Dfp1.