Protein phosphatase 4 promotes chromosome pairing and synapsis, and contributes to maintaining crossover competence with increasing age.
Protein phosphatase 4 promotes chromosome pairing and synapsis, and contributes to maintaining crossover competence with increasing age.
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DOI：
10.1371/journal.pgen.1004638
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发表时间：
2014-10
期刊：
影响因子：
4.5
通讯作者：
Carlton PM
中科院分区：
文献类型：
--
作者：
Sato-Carlton A;Li X;Crawley O;Testori S;Martinez-Perez E;Sugimoto A;Carlton PM
在减数分裂前，动态染色体重组包括配对、突触和父本染色体对的重组必须在减数分裂前期以高度调控的方式发生。染色体如何识别彼此的同源性，并与它们的同源伙伴独家配对和突触，同时拒绝与非同源染色体的非法突触，仍然不清楚。此外，重组起始和交叉形成的水平是如何被调节的，从而产生足够而不是有害的DNA断裂水平，并将其加工成交叉，目前还不清楚。我们发现在秀丽隐杆线虫中，高度保守的丝氨酸/苏氨酸蛋白磷酸酶PP4同源物PPH-4.1需要独立执行涉及减数分裂染色体动力学的四个独立功能：(1)突触独立的染色体配对，(2)突触对同源染色体的限制，(3)程序化的DNA双链断裂起始，以及(4)交叉形成。利用突变株的定量成像，包括染色体和突触复合体的超分辨率（3D-SIM）显微镜，我们发现在缺乏PPH-4.1活性的情况下，这些过程中独立产生的缺陷最终导致减数分裂不分离和胚胎致死。有趣的是，我们发现双链断裂起始和交叉形成的缺陷，而不是配对或突触，在老年突变动物的种系中变得更加严重，这表明随着母亲年龄的增加，对PPH-4.1的依赖性增加。我们的研究结果表明，PPH-4.1在减数分裂前期染色体动力学和维持减数分裂能力中起着多重独立的作用。PP4的高度保守性表明它可能是减数分裂前期染色体动力学的普遍调节因子。减数分裂通过将包含同源染色体对的二倍体基因组分配到只接收一条染色体的子细胞中来产生配子。为了在第一次减数分裂中正确分离，染色体必须与同源染色体配对并突触，并进行交叉重组，这需要断裂和修复所有染色体的DNA链。染色体如何识别它们的伴侣，以及细胞如何控制发生的DNA断裂和重组的数量，这些都是悬而未决的问题。在这项研究中，我们观察了秀丽隐杆线虫的减数分裂，以研究蛋白磷酸酶4 （PP4）的作用。我们发现，在缺乏PP4的情况下，染色体经常与非同源染色体配对并突触，或者折叠成一半与自己突触。此外，没有PP4活性，DNA断裂和交叉重组事件的数量都独立减少。随着年龄的增长，后两种缺陷变得更加严重，这表明老年动物对PP4的需求更大。这些发现揭示了蛋白质磷酸化如何控制减数分裂事件，并展示了PP4意想不到的重要作用。
Prior to the meiotic divisions, dynamic chromosome reorganizations including pairing, synapsis, and recombination of maternal and paternal chromosome pairs must occur in a highly regulated fashion during meiotic prophase. How chromosomes identify each other's homology and exclusively pair and synapse with their homologous partners, while rejecting illegitimate synapsis with non-homologous chromosomes, remains obscure. In addition, how the levels of recombination initiation and crossover formation are regulated so that sufficient, but not deleterious, levels of DNA breaks are made and processed into crossovers is not understood well. We show that in Caenorhabditis elegans, the highly conserved Serine/Threonine protein phosphatase PP4 homolog, PPH-4.1, is required independently to carry out four separate functions involving meiotic chromosome dynamics: (1) synapsis-independent chromosome pairing, (2) restriction of synapsis to homologous chromosomes, (3) programmed DNA double-strand break initiation, and (4) crossover formation. Using quantitative imaging of mutant strains, including super-resolution (3D-SIM) microscopy of chromosomes and the synaptonemal complex, we show that independently-arising defects in each of these processes in the absence of PPH-4.1 activity ultimately lead to meiotic nondisjunction and embryonic lethality. Interestingly, we find that defects in double-strand break initiation and crossover formation, but not pairing or synapsis, become even more severe in the germlines of older mutant animals, indicating an increased dependence on PPH-4.1 with increasing maternal age. Our results demonstrate that PPH-4.1 plays multiple, independent roles in meiotic prophase chromosome dynamics and maintaining meiotic competence in aging germlines. PP4's high degree of conservation suggests it may be a universal regulator of meiotic prophase chromosome dynamics. Meiosis creates gametes by distributing diploid genomes containing homologous chromosome pairs into daughter cells that receive only one of each chromosome. To segregate correctly at the first meiotic division, chromosomes must pair and synapse with their homologous partners, and undergo crossover recombination, which requires breaking and repairing the DNA strands of all chromosomes. How chromosomes recognize their partners, and how a cell controls the amount of DNA breakage and recombination that occurs, are open questions. In this study, we observed meiosis in the nematode Caenorhabditis elegans to examine the role of Protein Phosphatase 4 (PP4). We found that in the absence of PP4, chromosomes often paired and synapsed with non-homologous chromosomes, or synapsed with themselves by folding in half. Additionally, without PP4 activity, the number of DNA breaks and of crossover recombination events were both independently reduced. The latter two defects became even worse with increasing age, indicating that older animals require PP4 to a greater extent. These findings shed light on how protein phosphorylation controls meiotic events, and demonstrate unanticipated, important roles for PP4.
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影响因子：
4.5
作者：
Cheng EY;Hunt PA;Naluai-Cecchini TA;Fligner CL;Fujimoto VY;Pasternack TL;Schwartz JM;Steinauer JE;Woodruff TJ;Cherry SM;Hansen TA;Vallente RU;Broman KW;Hassold TJ
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Hassold TJ
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4.5
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通讯作者：
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作者：
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影响因子：
10.5
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通讯作者：
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11.8
作者：
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