The RecQ4 Orthologue Hrq1 Is Critical for DNA Interstrand Cross-Link Repair and Genome Stability in Fission Yeast
The RecQ4 Orthologue Hrq1 Is Critical for DNA Interstrand Cross-Link Repair and Genome Stability in Fission Yeast
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DOI：
10.1128/mcb.06184-11
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发表时间：
2012-01-01
影响因子：
5.3
通讯作者：
Boddy, Michael N.
中科院分区：
文献类型：
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作者：
Groocock, Lynda M.;Prudden, John;Boddy, Michael N.
在五个人类RecQ家族解旋酶中，RecQ4、BLM和WRN抑制不同的基因组不稳定相关疾病，这些疾病具有严重的表型，通常病因不明。在这里，我们从功能上定义了Hrq1，这是一种来自分裂酵母的RecQ4的新同源物。对Hrq1的生化分析显示，在不同的DNA底物上，包括气泡而不是钝化的双链，RecQ家族的特征是依赖于Deah盒和ATP的3‘-5’解旋酶活性。缺乏Hrq1的细胞遭受自发的基因组不稳定，因此，需要同源重组修复和DNA损伤检查点才能存活。Hrq1支持对化疗药物顺铂造成的DNA损伤的核苷酸切除修复，在某些遗传背景下，还支持紫外线。遗传上位性分析表明，Hrq1的作用与依赖于增殖细胞核抗原/UBC13/MMS2的复制后修复(PRR)途径平行。因此，在hrq1 Delta细胞中，损伤通过PRR途径传导，产生超重组和突变子表型；类似的缺陷可能是遗传不稳定性和与RecQ4功能障碍相关的疾病的基础。
Of the five human RecQ family helicases, RecQ4, BLM, and WRN suppress distinct genome instability-linked diseases with severe phenotypes, often with indeterminate etiologies. Here, we functionally define Hrq1, a novel orthologue of RecQ4 from fission yeast. Biochemical analysis of Hrq1 reveals a DEAH box- and ATP-dependent 3'-5' helicase activity on various DNA substrates, including bubbles but not blunt duplexes, characteristic of the RecQ family. Cells lacking Hrq1 suffer spontaneous genomic instability and, consequently, require homologous recombination repair and the DNA damage checkpoint for viability. Hrq1 supports the nucleotide excision repair of DNA damage caused by the chemotherapeutic agent cisplatin and, in certain genetic contexts, UV light. Genetic epistasis analyses reveal that Hrq1 acts parallel to the PCNA/Ubc13/Mms2-dependent postreplication repair (PRR) pathway. Thus, in hrq1 Delta cells, lesions are channeled through the PRR pathway, yielding hyper-recombinant and mutator phenotypes; analogous defects may underlie the genetic instability and diseases associated with RecQ4 dysfunction.