Recql5突变体可促进小鼠子代中复杂的CRISPR/Cas9介导的染色体工程。

IF 3.3 3区生物学

Genetics Pub Date : 2024-04-05 DOI:10.1093/genetics/iyae054

Satoru Iwata, Miki Nagahara, Risako Ido, Takashi Iwamoto

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引用次数: 0

摘要

在癌症和先天性疾病患者的临床样本中经常可以观察到复杂染色体重排（CCR），但很难通过实验诱导。在这里，我们首次成功建立了 CCRs 动物模型。Recql5是参与DNA复制、转录和修复的DNA螺旋酶RecQ家族的一个重要成员，它的突变使CRISPR/Cas9介导的CCR成为可能，从而建立了一个包含三重融合基因和巨碱基大小倒位的小鼠模型。单个染色体重排的这些结构特征中，有一些使用了模板切换和微组学介导的断裂诱导复制机制，让人联想到新近描述的 "染色体合成"（chromoanasynthesis）现象。这些数据表明，Recql5突变体小鼠可以成为分析CCR（尤其是染色体合成）发病机制的有力工具，因为人们对CCR的内在机制知之甚少。本研究中产生的 Recql5 突变体将被存放在重要的动物研究机构，从而使它们能够用于未来的 CCRs 研究。

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A Recql5 mutant facilitates complex CRISPR/Cas9-mediated-chromosomal engineering in mouse zygotes.

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.

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来源期刊

Genetics 生物-遗传学

CiteScore

6.20

自引率

6.10%

发文量

177

期刊介绍： GENETICS is published by the Genetics Society of America, a scholarly society that seeks to deepen our understanding of the living world by advancing our understanding of genetics. Since 1916, GENETICS has published high-quality, original research presenting novel findings bearing on genetics and genomics. The journal publishes empirical studies of organisms ranging from microbes to humans, as well as theoretical work. While it has an illustrious history, GENETICS has changed along with the communities it serves: it is not your mentor''s journal. The editors make decisions quickly – in around 30 days – without sacrificing the excellence and scholarship for which the journal has long been known. GENETICS is a peer reviewed, peer-edited journal, with an international reach and increasing visibility and impact. All editorial decisions are made through collaboration of at least two editors who are practicing scientists. GENETICS is constantly innovating: expanded types of content include Reviews, Commentary (current issues of interest to geneticists), Perspectives (historical), Primers (to introduce primary literature into the classroom), Toolbox Reviews, plus YeastBook, FlyBook, and WormBook (coming spring 2016). For particularly time-sensitive results, we publish Communications. As part of our mission to serve our communities, we''ve published thematic collections, including Genomic Selection, Multiparental Populations, Mouse Collaborative Cross, and the Genetics of Sex.