SHOC1 is a ERCC4-(HhH)2-like protein, integral to the formation of crossover recombination intermediates during mammalian meiosis.
SHOC1 is a ERCC4-(HhH)2-like protein, integral to the formation of crossover recombination intermediates during mammalian meiosis.
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DOI：
10.1371/journal.pgen.1007381
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发表时间：
2018-05
期刊：
影响因子：
4.5
通讯作者：
Pezza RJ
中科院分区：
文献类型：
--
作者：
Guiraldelli MF;Felberg A;Almeida LP;Parikh A;de Castro RO;Pezza RJ
减数分裂过程中的染色体分离错误导致非整倍体配子的形成，是人类流产和出生缺陷的主要原因。正确的染色体分离需要母本和父本同源染色体的成对关联。交叉是交叉 (CO) 的细胞学表现，它提供了一种物理连接，将同源物作为一对结合在一起，促进它们在减数分裂 I 时在纺锤体上的定向。虽然交叉促进活动确保了 CO 的数量和位置平衡，但它们在哺乳动物中的身份和作用机制仍未得到充分研究。先前在酵母和拟南芥中的研究表明，Zip2 和 Shoc1 是直系同源蛋白，在促进 CO 形成中发挥重要作用。我们的工作是第一项针对哺乳动物的研究，显示小鼠和人类 SHOC1 的体内和体外功能。我们发现，纯化的重组人 SHOC1（XPF/MUS81 家族成员）优先结合分支 DNA 分子，但显然缺乏体外核酸内切酶活性，尽管其具有保守的 ERCC4-(HhH)2 核心结构。细胞学观察表明，SHOC1 低效小鼠的大多数精母细胞中重组的初始步骤是正常的。然而，重组的后期出现异常，因为 MLH1 的染色体定位减少。一致地，交叉形成减少，细胞停滞在中期 I，有一些滞后染色体和随后的细胞凋亡。对 SHOC1 缺陷小鼠的分析以及 SHOC1 选择性定位到重组位点的子集表明 SHOC1 在 CO 形成过程的关键中期步骤中发挥作用。染色体轴向元件的形成和同源配对显然是正常的，但突触因 SYCP1 的改变而经常无法延伸染色体轴的全长。最后，我们描述了 SHOC1 与 TEX11（另一种对 CO 形成很重要的蛋白质）相互作用，将 SHOC1 与染色体轴和结构连接起来。减数分裂是一种特殊类型的细胞分裂，其中产生单倍体配子以平衡受精时发生的染色体数目加倍。正确的染色体分离需要母本和父本同源染色体的成对关联。这是由交叉（chiasmata）提供的，交叉是由于同源重组介导的双链 DNA 断裂（DSB）修复而产生的。减数分裂染色体通过交叉连接成对，保证每个配子仅接收每条染色体的一个副本。因此，重组错误通常与自然流产、非整倍体出生缺陷以及某些情况下的不孕症有关。我们观察到 SHOC1 的缺失会导致重组缺陷和染色体结构减数分裂特异性修饰不完整。因此，我们的研究结果表明，小鼠 SHOC1 蛋白是减数分裂重要方面正常进展所必需的，其作用是确保正确数量的染色体转移到下一代。
Chromosome segregation errors during meiosis result in the formation of aneuploid gametes and are the leading cause of pregnancy loss and birth defects in humans. Proper chromosome segregation requires pairwise associations of maternal and paternal homologous chromosomes. Chiasmata, which are the cytological manifestations of crossovers (COs), provide a physical link that holds the homologs together as a pair, facilitating their orientation on the spindle at meiosis I. Although CO-promoting activities ensure a balanced number and position of COs, their identity and mechanism of action in mammals remain understudied. Previous work in yeast and Arabidopsis has shown that Zip2 and Shoc1 are ortholog proteins with an important role in promoting the formation of COs. Our work is the first study in mammals showing the in vivo and in vitro function of mouse and human SHOC1. We show that purified recombinant human SHOC1, an XPF/MUS81 family member, preferentially binds branched DNA molecules but apparently lacks in vitro endonuclease activity, despite its conserved ERCC4-(HhH)2 core structure. Cytological observations suggest that initial steps of recombination are normal in a majority of spermatocytes from SHOC1 hypomorphic mice. However, late stages of recombination appear abnormal, as chromosomal localization of MLH1 is reduced. In agreement, chiasma formation is reduced, and cells arrest at metaphase I with a few lagging chromosomes and subsequent apoptosis. This analysis of SHOC1-deficient mice and the selective localization of SHOC1 to a subset of recombination sites show that SHOC1 acts at key mid-stage steps of the CO formation process. The formation of chromosome axial elements and homologous pairing are apparently normal, but synapsis is altered with SYCP1 frequently failing to extend the full length of the chromosome axes. Finally, we describe that SHOC1 interacts with TEX11, another protein important for the formation of COs, connecting SHOC1 to chromosome axis and structure. Meiosis is a specialized type of cell division in which haploid gametes are generated to counterbalance the doubling of the chromosome number occurring at fertilization. Proper chromosome segregation requires pairwise associations of the maternal and paternal homologous chromosomes. This is provided by chiasmata, which are generated as a result of homologous recombination-mediated repair of double-strand DNA breaks (DSBs). The association of meiotic chromosomes in pairs through chiasmata guarantees that each gamete receives only one copy of each chromosome. For this reason, errors in recombination are commonly linked to spontaneous abortions, aneuploid-based birth defects, and in some cases, infertility. We observed that the absence of SHOC1 results in deficient recombination and incomplete meiosis-specific modification of chromosome structure. Our findings thus indicate that the mouse SHOC1 protein is required for normal progression of important aspects of meiosis that act to ensure that the correct numbers of chromosomes are transferred to the next generation.
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