UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination
UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination
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DOI：
10.1073/pnas.0910267107
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发表时间：
2010-02-02
影响因子：
11.1
通讯作者：
Kwon, Yong Tae
中科院分区：
文献类型：
--
作者：
An, Jee Young;Kim, Eun-A.;Kwon, Yong Tae
组蛋白的泛素化提供了一种调节染色质重塑和基因表达的重要机制。近期研究已揭示了参与组蛋白泛素化的泛素连接酶，但在精子发生过程中起作用的相关酶以及组蛋白泛素化的功能仍不清楚。我们先前已表明，缺乏泛素连接酶UBR2（N - 端规则蛋白水解途径的识别E3成分之一）的小鼠不育，其在减数分裂前期I停滞。在此我们表明，UBR2定位于减数分裂染色质区域，包括与染色质失活相关的未联会的轴元件，并通过组蛋白H2A的泛素化介导转录沉默。UBR2与泛素结合酶HR6B及其底物H2A相互作用，促进HR6B - H2A相互作用以及泛素从HR6B到H2A的转移。UBR2和泛素化的H2A（uH2A）在时空上标记受转录沉默影响的减数分裂染色质区域，并且UBR2缺陷型精母细胞在减数分裂过程中无法诱导H2A的泛素化。UBR2缺陷型精母细胞在与X和Y染色体未联会轴相关的基因的全染色体转录沉默方面严重受损。我们的研究结果表明，依赖UBR2的组蛋白泛素化不足会触发粗线期检查点系统，为染色质重塑和基因表达调控提供了新的见解。
Ubiquitination of histones provides an important mechanism regulating chromatin remodeling and gene expression. Recent studies have revealed ubiquitin ligases involved in histone ubiquitination, yet the responsible enzymes and the function of histone ubiquitination in spermatogenesis remain unclear. We have previously shown that mice lacking the ubiquitin ligase UBR2, one of the recognition E3 components of the N-end rule proteolytic pathway, are infertile associated with meiotic arrest at prophase I. We here show that UBR2 localizes to meiotic chromatin regions, including unsynapsed axial elements linked to chromatin inactivation, and mediates transcriptional silencing via the ubiquitination of histone H2A. UBR2 interacts with the ubiquitin conjugating enzyme HR6B and its substrate H2A and promotes the HR6B-H2A interaction and the HR6B-to-H2A transfer of ubiquitin. UBR2 and ubiquitinated H2A (uH2A) spatiotemporally mark meiotic chromatin regions subject to transcriptional silencing, and UBR2-deficient spermatocytes fail to induce the ubiquitination of H2A during meiosis. UBR2-deficient spermatocytes are profoundly impaired in chromosome-wide transcriptional silencing of genes linked to unsynapsed axes of the X and Y chromosomes. Our findings suggest that insufficiency in UBR2-dependent histone ubiquitination triggers a pachytene checkpoint system, providing a new insight into chromatin remodeling and gene expression regulation.