Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR).
Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR).
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DOI：
10.1098/rsob.130019
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发表时间：
2013-07-31
期刊：
影响因子：
5.8
通讯作者：
Neale MJ
中科院分区：
文献类型：
--
作者：
Gray S;Allison RM;Garcia V;Goldman AS;Neale MJ
在减数分裂过程中，程序性DNA双链断裂（DSB）的形成和修复产生同源染色体之间的遗传交换，这一过程对于减数分裂染色体分离和产生遗传多样性的有性生殖群体至关重要。减数分裂DSB的形成是一个复杂的过程，需要多种蛋白质，其中Spo 11是进化上保守的催化亚基。Spo11及其辅助蛋白的确切功能或调节方式尚不清楚。在这里，我们使用酿酒酵母揭示，减数分裂DSB的形成是由Mec 1（ATR）分支的DNA损伤信号级联，促进DSB的形成时，Spo11介导的催化受到损害。正反馈途径的激活与单链DNA（ssDNA）重组中间体的形成和下游激酶Mek1的激活相关。我们表明，检查点激活的要求可以通过删除NDT 80转录因子延长减数分裂前期获救，即使是短暂的前期逮捕造成的NDT 80耗尽是足以恢复减数分裂孢子活力检查点突变体。我们的观察结果是出乎意料的，最近的报告，互补激酶途径Tel 1（ATM）的行为，以抑制DSB的形成。我们建议，这种拮抗调节DSB形成Mec1和Tel 1创建一个监管机制，DSB的绝对频率保持在最佳水平的遗传交换和有效的染色体分离。
During meiosis, formation and repair of programmed DNA double-strand breaks (DSBs) create genetic exchange between homologous chromosomes—a process that is critical for reductional meiotic chromosome segregation and the production of genetically diverse sexually reproducing populations. Meiotic DSB formation is a complex process, requiring numerous proteins, of which Spo11 is the evolutionarily conserved catalytic subunit. Precisely how Spo11 and its accessory proteins function or are regulated is unclear. Here, we use Saccharomyces cerevisiae to reveal that meiotic DSB formation is modulated by the Mec1(ATR) branch of the DNA damage signalling cascade, promoting DSB formation when Spo11-mediated catalysis is compromised. Activation of the positive feedback pathway correlates with the formation of single-stranded DNA (ssDNA) recombination intermediates and activation of the downstream kinase, Mek1. We show that the requirement for checkpoint activation can be rescued by prolonging meiotic prophase by deleting the NDT80 transcription factor, and that even transient prophase arrest caused by Ndt80 depletion is sufficient to restore meiotic spore viability in checkpoint mutants. Our observations are unexpected given recent reports that the complementary kinase pathway Tel1(ATM) acts to inhibit DSB formation. We propose that such antagonistic regulation of DSB formation by Mec1 and Tel1 creates a regulatory mechanism, where the absolute frequency of DSBs is maintained at a level optimal for genetic exchange and efficient chromosome segregation.
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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：
3.8
作者：
Keelagher, Rebecca E.;Cotton, Victoria E.;Borts, Rhona H.
通讯作者：
Borts, Rhona H.
影响因子：
10.5
作者：
Benjamin, KR;Zhang, C;Herskowitz, I
通讯作者：
Herskowitz, I
影响因子：
56.9
作者：
Borde, V;Goldman, ASH;Lichten, M
通讯作者：
Lichten, M
DOI：
10.1083/jcb.201104121
发表时间：
2011-10-31
期刊：
The Journal of cell biology
影响因子：
--
作者：
Joyce EF;Pedersen M;Tiong S;White-Brown SK;Paul A;Campbell SD;McKim KS
通讯作者：
McKim KS