Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE, Leiden, The Netherlands.
Nat Commun. 2021 Dec 8;12(1):7126. doi: 10.1038/s41467-021-27408-z.
DNA double-strand breaks are a major threat to cellular survival and genetic integrity. In addition to high fidelity repair, three intrinsically mutagenic DNA break repair routes have been described, i.e. single-strand annealing (SSA), polymerase theta-mediated end-joining (TMEJ) and residual ill-defined microhomology-mediated end-joining (MMEJ) activity. Here, we identify C. elegans Helicase Q (HELQ-1) as being essential for MMEJ as well as for SSA. We also find HELQ-1 to be crucial for the synthesis-dependent strand annealing (SDSA) mode of homologous recombination (HR). Loss of HELQ-1 leads to increased genome instability: patchwork insertions arise at deletion junctions due to abortive rounds of polymerase theta activity, and tandem duplications spontaneously accumulate in genomes of helq-1 mutant animals as a result of TMEJ of abrogated HR intermediates. Our work thus implicates HELQ activity for all DSB repair modes guided by complementary base pairs and provides mechanistic insight into mutational signatures common in HR-defective cancers.
DNA 双链断裂是细胞生存和遗传完整性的主要威胁。除了高保真修复外，还描述了三种内在的具有突变性的 DNA 断裂修复途径，即单链退火（SSA）、聚合酶θ介导的末端连接（TMEJ）和残余定义不明确的微同源介导的末端连接（MMEJ）活性。在这里，我们确定线虫的解旋酶 Q（HELQ-1）对于 MMEJ 以及 SSA 是必需的。我们还发现 HELQ-1 对于合成依赖性链退火（SDSA）同源重组（HR）模式至关重要。HELQ-1 的缺失会导致基因组不稳定性增加：由于聚合酶θ活性的失败回合，在缺失连接处会出现补丁状插入，并且由于 HR 中间产物的 TMEJ 而导致 tandem 重复在 helq-1 突变体动物的基因组中自发积累。因此，我们的工作表明 HELQ 活性对于所有由互补碱基对指导的 DSB 修复模式都是必需的，并为 HR 缺陷型癌症中常见的突变特征提供了机制上的见解。
