Hrq1/RECQL4 regulation is critical for preventing aberrant recombination during DNA intrastrand crosslink repair and is upregulated in breast cancer.
Hrq1/RECQL4 regulation is critical for preventing aberrant recombination during DNA intrastrand crosslink repair and is upregulated in breast cancer.
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DOI：
10.1371/journal.pgen.1010122
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发表时间：
2022-09
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
人类RECQL4是DNA解旋酶RecQ家族的一员，在DNA复制和修复过程中起作用。RECQL4突变与发育缺陷和癌症有关。虽然RECQL4突变导致疾病，但在癌症中也观察到RECQL4过表达，包括乳腺癌和前列腺癌。因此，严格调控RECQL4蛋白水平对基因组稳定至关重要。由于哺乳动物的RECQL4至关重要，细胞如何调节RECQL4蛋白水平在很大程度上是未知的。利用芽殖酵母，我们研究了RECQL4同源物HRQ1在DNA交联修复过程中的作用。我们发现Hrq1在无错误模板切换途径中起作用，介导DNA链内交联修复。虽然Hrq1介导顺铂诱导病变的修复，但它在顺铂治疗后却被蛋白酶体降解。通过鉴定目标赖氨酸残基，我们发现阻止Hrq1降解导致重组和诱变增加。和酵母一样，人类的RECQL4在接触交联剂后也会被降解。此外，过表达RECQL4导致RAD51病灶增加，这取决于其解旋酶活性。通过生物信息学分析，我们观察到RECQL4过表达与重组和突变增加相关。总的来说，我们的研究揭示了Hrq1/RECQL4在DNA链内交联修复中的作用，并进一步了解了RECQL4的错误调节如何促进基因组不稳定性，这是癌症的标志。RECQL4是一种DNA解旋酶，在DNA复制和修复过程中起作用。虽然在以发育缺陷和癌症为特征的疾病（如rothmond - thomson综合征）中发现了功能丧失的RECQL4突变，但在癌症（如乳腺癌）中也观察到过表达的RECQL4。因此，必须严格调控RECQL4蛋白的表达。在这里，我们使用了RECQL4和Hrq1的芽殖酵母同源物，发现Hrq1蛋白水平的过表达导致重组和突变增加，这两者都是癌症的标志。我们发现Hrq1的功能是介导一种特定类型的DNA损伤的修复，即链内交联，当同一链上的DNA核苷酸化学连接在一起时发生。这些发现在人类中也是保守的，表明酵母Hrq1和人类RECQL4之间存在共同的机制。总的来说，我们的研究确定了RECQL4在DNA链内交联修复中的保守作用，并为其错误调控如何促进癌症发展提供了见解。
Human RECQL4 is a member of the RecQ family of DNA helicases and functions during DNA replication and repair. RECQL4 mutations are associated with developmental defects and cancer. Although RECQL4 mutations lead to disease, RECQL4 overexpression is also observed in cancer, including breast and prostate. Thus, tight regulation of RECQL4 protein levels is crucial for genome stability. Because mammalian RECQL4 is essential, how cells regulate RECQL4 protein levels is largely unknown. Utilizing budding yeast, we investigated the RECQL4 homolog, HRQ1, during DNA crosslink repair. We find that Hrq1 functions in the error-free template switching pathway to mediate DNA intrastrand crosslink repair. Although Hrq1 mediates repair of cisplatin-induced lesions, it is paradoxically degraded by the proteasome following cisplatin treatment. By identifying the targeted lysine residues, we show that preventing Hrq1 degradation results in increased recombination and mutagenesis. Like yeast, human RECQL4 is similarly degraded upon exposure to crosslinking agents. Furthermore, over-expression of RECQL4 results in increased RAD51 foci, which is dependent on its helicase activity. Using bioinformatic analysis, we observe that RECQL4 overexpression correlates with increased recombination and mutations. Overall, our study uncovers a role for Hrq1/RECQL4 in DNA intrastrand crosslink repair and provides further insight how misregulation of RECQL4 can promote genomic instability, a cancer hallmark. RECQL4 is a DNA helicase and functions during DNA replication and repair. While loss-of-function RECQL4 mutations are found in diseases characterized by developmental defects and cancer, such as Rothmund-Thomson syndrome, over-expression of RECQL4 is also observed in cancer, such as breast cancer. Therefore, RECQL4 protein expression must be tightly regulated. Here we used the budding yeast homolog of RECQL4, Hrq1, and discovered that overexpression of Hrq1 protein levels result in increased recombination and mutations, both cancer hallmarks. We find that Hrq1 functions to mediate repair of a specific type of DNA damage, intrastrand crosslinks, which occur when DNA nucleotides on the same strand are chemically linked together. These findings are also conserved in humans suggesting a common mechanism between yeast Hrq1 and human RECQL4. Overall, our study identifies a conserved role for RECQL4 in DNA intrastrand crosslink repair and provides insights into how its misregulation could promote cancer development.
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