The human genome encodes five RecQ helicases (RECQL1, BLM, WRN, RECQL4, and RECQL5) that participate in various processes underpinning genomic stability. Of these enzymes, the disease-associated RECQL4 is comparatively understudied due to a variety of technical challenges. However, Saccharomyces cerevisiae encodes a functional homolog of RECQL4 called Hrq1, which is more amenable to experimentation and has recently been shown to be involved in DNA inter-strand crosslink (ICL) repair and telomere maintenance. To expand our understanding of Hrq1 and the RecQ4 subfamily of helicases in general, we took a multi-omics approach to define the Hrq1 interactome in yeast. Using synthetic genetic array analysis, we found that mutations of genes involved in processes such as DNA repair, chromosome segregation, and transcription synthetically interact with deletion of HRQ1 and the catalytically inactive hrq1-K318A allele. Pull-down of tagged Hrq1 and mass spectrometry identification of interacting partners similarly underscored links to these processes and others. Focusing on transcription, we found that hrq1 mutant cells are sensitive to caffeine and that mutation of HRQ1 alters the expression levels of hundreds of genes. In the case of hrq1-K318A, several of the most highly upregulated genes encode proteins of unknown function whose expression levels are also increased by DNA ICL damage. Together, our results suggest a heretofore unrecognized role for Hrq1 in transcription, as well as novel members of the Hrq1 ICL repair pathway. These data expand our understanding of RecQ4 subfamily helicase biology and help to explain why mutations in human RECQL4 cause diseases of genomic instability.

人类基因组编码了五种RecQ解旋酶（RECQL1，BLM，WRN，RECQL4和RECQL5），它们参与了支持基因组稳定性的各种过程。在这些酶中，由于各种技术挑战，与疾病相关的RECQL4的研究相对较少。但是，酿酒酵母编码一个称为Hrq1的RECQL4的功能同源物，该同源物更适合进行实验，最近被证明参与DNA链间交联（ICL）修复和端粒维护。为了扩大我们对解旋酶的Hrq1和RecQ4亚家族的了解，我们采取了一种多组学方法来定义酵母中的Hrq1相互作用基因组。使用合成遗传阵列分析，我们发现参与DNA修复，染色体分离和转录等过程的基因突变与HRQ1的缺失和具有催化活性的hrq1-K318A缺失合成相互作用等位基因。标记Hrq1的下拉和相互作用伙伴的质谱鉴定同样强调了与这些过程及其他过程的联系。着眼于转录，我们发现hrq1突变细胞对咖啡因敏感，而HRQ1的突变改变了数百个基因的表达水平。在hrq1-K318A的情况下，一些高度上调的基因编码功能未知的蛋白质，其表达水平也因DNA ICL损伤而增加。在一起，我们的结果表明，Hrq1在转录中以及Hrq1 ICL修复途径的新成员迄今尚未被认识的作用。这些数据扩大了我们对RecQ4亚家族解旋酶生物学的理解，并有助于解释为什么人类RECQL4中的突变会导致基因组不稳定的疾病。