C. elegans germ cells switch between distinct modes of double-strand break repair during meiotic prophase progression.
C. elegans germ cells switch between distinct modes of double-strand break repair during meiotic prophase progression.
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DOI：
10.1371/journal.pgen.0030191
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发表时间：
2007-11
期刊：
影响因子：
4.5
通讯作者：
Villeneuve AM
中科院分区：
文献类型：
--
作者：
Hayashi M;Chin GM;Villeneuve AM
有性生殖过程中的染色体遗传依赖于有意诱导双链DNA断裂（DSB）和修复这些断裂的一个子集作为同源物间的交叉（CO）。在这里，我们提供了一个直接的示范，根据我们的RAD-50突变体的分析，在秀丽隐杆线虫减数分裂程序涉及收购和损失的一个专门的双链断裂修复模式（DSBR）。在减数分裂前的生殖细胞中，RAD-50不需要在自发或电离辐射（IR）诱导的DSB位点加载链交换蛋白RAD-51。一个专门的减数分裂DSBR模式在减数分裂前期开始时进行，与减数分裂染色体轴结构的组装一致。这种减数分裂DSBR模式的特征在于依赖RAD-50在DSB位点快速积累RAD-51和将DSB转化为同源物CO的能力。在粗线期中期到粗线期晚期的过渡期，生殖细胞经历从减数分裂DSBR模式的突然释放，其特征在于回复到RAD-51的RAD-50-独立加载和丧失将DSB转化为同源物CO的能力。DSBR模式中的这种转变依赖于MAP激酶触发的前期进展，并且在时间上与染色体结构的主要重塑一致。我们提出，至少有两个发育编程开关DSBR模式，可能赋予染色体结构的变化，在C。elegans种系，以允许形成减数分裂交叉而不危害基因组的完整性。我们的数据进一步表明，减数分裂凝聚素组分REC-8可能在限制SPO-11产生减数分裂DSB的活性中起作用，RAD-50可能在抵消这种抑制中起作用。在有性生殖过程中染色体的忠实遗传取决于双链DNA断裂（DSB）的故意形成和随后通过导致同源染色体对之间交叉的机制修复这些断裂的子集。为了确保染色体分离而进行杂交的要求对有性繁殖的生物体构成了挑战，因为DSB在其他情况下对基因组完整性构成了危险。这份手稿提供了深入了解的机制，使生殖细胞产生重组为基础的联系，确保染色体遗传，同时保护其基因组的完整性。具体来说，我们提供了一个直接的示范，根据我们的rad-50突变体的分析，在C。秀丽线虫涉及双链断裂修复（DSBR）的特化减数分裂模式的获得和丧失。我们建议，在减数分裂前期的后期阶段恢复到约束较少的DSBR环境的能力作为保护基因组的故障安全机制，因为它提供了一个机会，以修复任何剩余的DBS和恢复染色体完整性之前，染色体分离。
Chromosome inheritance during sexual reproduction relies on deliberate induction of double-strand DNA breaks (DSBs) and repair of a subset of these breaks as interhomolog crossovers (COs). Here we provide a direct demonstration, based on our analysis of rad-50 mutants, that the meiotic program in Caenorhabditis elegans involves both acquisition and loss of a specialized mode of double-strand break repair (DSBR). In premeiotic germ cells, RAD-50 is not required to load strand-exchange protein RAD-51 at sites of spontaneous or ionizing radiation (IR)-induced DSBs. A specialized meiotic DSBR mode is engaged at the onset of meiotic prophase, coincident with assembly of meiotic chromosome axis structures. This meiotic DSBR mode is characterized both by dependence on RAD-50 for rapid accumulation of RAD-51 at DSB sites and by competence for converting DSBs into interhomolog COs. At the mid-pachytene to late pachytene transition, germ cells undergo an abrupt release from the meiotic DSBR mode, characterized by reversion to RAD-50-independent loading of RAD-51 and loss of competence to convert DSBs into interhomolog COs. This transition in DSBR mode is dependent on MAP kinase-triggered prophase progression and coincides temporally with a major remodeling of chromosome architecture. We propose that at least two developmentally programmed switches in DSBR mode, likely conferred by changes in chromosome architecture, operate in the C. elegans germ line to allow formation of meiotic crossovers without jeopardizing genomic integrity. Our data further suggest that meiotic cohesin component REC-8 may play a role in limiting the activity of SPO-11 in generating meiotic DSBs and that RAD-50 may function in counteracting this inhibition. Faithful inheritance of chromosomes during sexual reproduction depends on the deliberate formation of double-strand DNA breaks (DSBs) and subsequent repair of a subset of these breaks by a mechanism that leads to crossovers between homologous chromosome pairs. The requirement for crossovers to ensure chromosome segregation poses a challenge for sexually reproducing organisms, as DSBs constitute a danger to genomic integrity in other contexts. This manuscript provides insight into the mechanisms that allow germ cells to generate recombination-based linkages that ensure chromosome inheritance while at the same time protecting the integrity of their genomes. Specifically, we provide a direct demonstration, based on our analysis of rad-50 mutants, that the meiotic program in C. elegans involves both acquisition and loss of a specialized meiotic mode of double-strand break repair (DSBR). We propose that the ability to revert to a less constrained DSBR environment at a late stage of meiotic prophase serves as a fail-safe mechanism for safeguarding the genome, as it provides an opportunity to repair any remaining DBSs and restore chromosome integrity prior to chromosome segregation.
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