Four-pronged negative feedback of DSB machinery in meiotic DNA-break control in mice.
Four-pronged negative feedback of DSB machinery in meiotic DNA-break control in mice.
复制标题
DOI：
10.1093/nar/gkab082
复制
发表时间：
2021-03-18
影响因子：
14.9
通讯作者：
Tóth A
中科院分区：
文献类型：
--
作者：
Dereli I;Stanzione M;Olmeda F;Papanikos F;Baumann M;Demir S;Carofiglio F;Lange J;de Massy B;Baarends WM;Turner J;Rulands S;Tóth A
在大多数分类群中，减数分裂期间染色体数目减半需要同源染色体配对并形成交换。交叉来自程序性DNA双链断裂（DSB）的重组介导的修复。DSB由SPO11产生，其活性需要称为前DSB重组体的辅助蛋白复合物。为了阐明DSB机制的时空控制，我们集中在一个必不可少的SPO11辅助蛋白，IHO 1，它作为前DSB重组体的主要锚的染色体核心，称为轴。我们发现DSB通过至少四种不同的途径限制小鼠的DSB机制。首先，通过激活DNA损伤反应（DDR）激酶ATM，DSB限制了前DSB重组体的数量，而不影响IHO 1。其次，在其附近，DSB主要通过另一种DDR激酶ATR触发IHO 1消耗。第三，DSB使同源突触成为可能，这促进了IHO 1和前DSB重组体从突触轴的消耗。最后，DSB和三种DDR激酶ATM、ATR和PRKDC能够从所有轴上对IHO 1进行阶段特异性消耗。我们假设，这四个负反馈途径保护基因组的完整性，确保DSB的形式没有过量，分布均匀，并限于基因组的位置和前期阶段，DSB的功能，促进同源配对和交叉形成。
In most taxa, halving of chromosome numbers during meiosis requires that homologous chromosomes (homologues) pair and form crossovers. Crossovers emerge from the recombination-mediated repair of programmed DNA double-strand breaks (DSBs). DSBs are generated by SPO11, whose activity requires auxiliary protein complexes, called pre-DSB recombinosomes. To elucidate the spatiotemporal control of the DSB machinery, we focused on an essential SPO11 auxiliary protein, IHO1, which serves as the main anchor for pre-DSB recombinosomes on chromosome cores, called axes. We discovered that DSBs restrict the DSB machinery by at least four distinct pathways in mice. Firstly, by activating the DNA damage response (DDR) kinase ATM, DSBs restrict pre-DSB recombinosome numbers without affecting IHO1. Secondly, in their vicinity, DSBs trigger IHO1 depletion mainly by another DDR kinase, ATR. Thirdly, DSBs enable homologue synapsis, which promotes the depletion of IHO1 and pre-DSB recombinosomes from synapsed axes. Finally, DSBs and three DDR kinases, ATM, ATR and PRKDC, enable stage-specific depletion of IHO1 from all axes. We hypothesize that these four negative feedback pathways protect genome integrity by ensuring that DSBs form without excess, are well-distributed, and are restricted to genomic locations and prophase stages where DSBs are functional for promoting homologue pairing and crossover formation.
登录
查看更多内容
影响因子：
64.8
作者：
Garcia V;Gray S;Allison RM;Cooper TJ;Neale MJ
通讯作者：
Neale MJ
影响因子：
4.5
作者：
Carballo JA;Panizza S;Serrentino ME;Johnson AL;Geymonat M;Borde V;Klein F;Cha RS
通讯作者：
Cha RS
影响因子：
64.8
作者：
Acquaviva, Laurent;Boekhout, Michiel;Keeney, Scott
通讯作者：
Keeney, Scott
影响因子：
4.4
作者：
Kumar, Rajeev;Oliver, Cecilia;de Massy, Bernard
通讯作者：
de Massy, Bernard
影响因子：
4.5
作者：
Barchi M;Roig I;Di Giacomo M;de Rooij DG;Keeney S;Jasin M
通讯作者：
Jasin M