Abstract:
Complex chromosomal rearrangements (CCRs) are often observed in clinical samples from patients with cancer and congenital diseases but are difficult to induce experimentally. Here, we report the first success in establishing animal models for CCRs. Mutation in Recql5, a crucial member of the DNA helicase RecQ family involved in DNA replication, transcription, and repair, enabled CRISPR/Cas9-mediated CCRs, establishing a mouse model containing triple fusion genes and megabase-sized inversions. Some of these structural features of individual chromosomal rearrangements use template switching and microhomology-mediated break-induced replication mechanisms and are reminiscent of the newly described phenomenon \"chromoanasynthesis.\" These data show that Recql5 mutant mice could be a powerful tool to analyze the pathogenesis of CCRs (particularly chromoanasynthesis) whose underlying mechanisms are poorly understood. The Recql5 mutants generated in this study are to be deposited at key animal research facilities, thereby making them accessible for future research on CCRs.
摘要:
复杂的染色体重排(CCR)通常在癌症和先天性疾病患者的临床样品中观察到,但难以通过实验诱导。这里,我们报道了建立CCRs动物模型的首次成功。Recql5是参与DNA复制的DNA解旋酶RecQ家族的关键成员,转录,修复,启用CRISPR/Cas9介导的CCR,建立含有三重融合基因和megabase大小倒位的小鼠模型。单个染色体重排的这些结构特征中的一些使用模板转换和微同源性介导的断裂诱导的复制机制,让人想起了新描述的“染色体异步”现象。“这些数据表明,Recql5突变小鼠可能是分析CCRs发病机理的强大工具(特别是染色体异步),其潜在机制知之甚少。本研究中产生的Recql5突变体将存放在关键的动物研究设施中,从而使它们可用于未来的CCR研究。