Distinct Functions in Regulation of Meiotic Crossovers for DNA Damage Response Clamp Loader Rad24(Rad17) and Mec1(ATR) Kinase
Distinct Functions in Regulation of Meiotic Crossovers for DNA Damage Response Clamp Loader Rad24(Rad17) and Mec1(ATR) Kinase
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DOI：
10.1534/genetics.119.302427
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发表时间：
2019-10
期刊：
影响因子：
3.3
通讯作者：
M. Shinohara;D. K. Bishop;A. Shinohara
中科院分区：
文献类型：
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作者：
M. Shinohara;D. K. Bishop;A. Shinohara
减数分裂交换（CO）的数量和分布是高度调节的，反映了第一轮减数分裂染色体分离对CO的需要。CO控制包括CO保证和CO干扰，其分别促进每个染色体至少一个CO二价和均匀间隔的CO。先前的研究揭示了DNA损伤反应（DDR）钳和钳加载器通过促进干扰CO和同源物间重组以及通过抑制异位重组在CO形成中的作用。在这项研究中，我们使用经典的酿酒酵母四分体分析表明，突变缺陷的RAD 24，它编码的DDR钳加载器（RAD 17在其他生物），显示减少CO频率在两个较短的染色体（III和V），但不是在一个长的染色体（染色体VII）。rad24突变体中的残留CO未显示干扰。与rad24相反，ATR激酶同源物Mec1中的缺陷突变体，包括mec1无效突变体和mec1激酶死亡突变体，在CO频率中显示出轻微或很少的缺陷。另一方面，与rad24突变体类似，mec1 CO显示干扰缺陷。我们的研究结果支持一个模型，其中DDR钳和钳装载蛋白促进干扰CO通过招募亲CO Zip，Mer和Msh蛋白的重组位点，而Mec1激酶调节CO分布的一个独特的机制。此外，CO的形成及其控制是以染色体特异性的方式实现的，这可能反映了染色体大小在调节中的作用。
The number and distribution of meiotic crossovers (COs) are highly regulated, reflecting the requirement for COs during the first round of meiotic chromosome segregation. CO control includes CO assurance and CO interference, which promote at least one CO per chromosome bivalent and evenly-spaced COs, respectively. Previous studies revealed a role for the DNA damage response (DDR) clamp and the clamp loader in CO formation by promoting interfering COs and interhomolog recombination, and also by suppressing ectopic recombination. In this study, we use classical tetrad analysis of Saccharomyces cerevisiae to show that a mutant defective in RAD24, which encodes the DDR clamp loader (RAD17 in other organisms), displayed reduced CO frequencies on two shorter chromosomes (III and V), but not on a long chromosome (chromosome VII). The residual COs in the rad24 mutant do not show interference. In contrast to rad24, mutants defective in the ATR kinase homolog Mec1, including a mec1 null and a mec1 kinase-dead mutant, show slight or few defects in CO frequency. On the other hand, mec1 COs show defects in interference, similar to the rad24 mutant. Our results support a model in which the DDR clamp and clamp-loader proteins promote interfering COs by recruiting pro-CO Zip, Mer, and Msh proteins to recombination sites, while the Mec1 kinase regulates CO distribution by a distinct mechanism. Moreover, CO formation and its control are implemented in a chromosome-specific manner, which may reflect a role for chromosome size in regulation.