美国纪念斯隆凯特琳癌症中心Maria Jasin和Scott Keeney研究团队提出小鼠生殖系重组热点的从头缺失和复制。2021年11月17日出版的《细胞》杂志发表了这一最新研究成果。

DNA 双链断裂 (DSB)后通常被忠实地修复，他们发现了一种不同类型的突变事件，其中通过连接来自单个热点内或相同或不同染色单体上相邻热点的两个紧密间隔的 DSB（双切割）的末端形成缺失。在没有 ATM 激酶的情况下，DSB 形成失调时缺失发生在正常减数分裂过程更频繁。染色体同系物之间的事件表明多染色单体损伤和中止的间隔修复。一些缺失包含来自其他热点的 DNA，表明远距离位点的双切割为插入诱变创造了底物。双切口末端连接也可以产生串联重复或染色体外环。他们的研究结果强调了 DSB 调控的重要性，并揭示了以前隐藏的减数分裂诱变可能影响人类健康和基因组进化的潜力。

据悉，许多 DSB在减数分裂期间出现以启动同源重组。

附：英文原文

Title: De novo deletions and duplications at recombination hotspots in mouse germlines

Author: Agnieszka Lukaszewicz, Julian Lange, Scott Keeney, Maria Jasin

Issue&Volume: 2021-11-17

Abstract: Numerous DNA double-strand breaks (DSBs) arise during meiosis to initiate homologousrecombination. These DSBs are usually repaired faithfully, but here, we uncover adistinct type of mutational event in which deletions form via joining of ends fromtwo closely spaced DSBs (double cuts) within a single hotspot or at adjacent hotspotson the same or different chromatids. Deletions occur in normal meiosis but are muchmore frequent when DSB formation is dysregulated in the absence of the ATM kinase.Events between chromosome homologs point to multi-chromatid damage and aborted gaprepair. Some deletions contain DNA from other hotspots, indicating that double cuttingat distant sites creates substrates for insertional mutagenesis. End joining at doublecuts can also yield tandem duplications or extrachromosomal circles. Our findingshighlight the importance of DSB regulation and reveal a previously hidden potentialfor meiotic mutagenesis that is likely to affect human health and genome evolution.

DOI: 10.1016/j.cell.2021.10.025

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01280-0