UBR2 of the N-end rule pathway is required for chromosome stability via histone ubiquitylation in spermatocytes and somatic cells.
UBR2 of the N-end rule pathway is required for chromosome stability via histone ubiquitylation in spermatocytes and somatic cells.
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DOI：
10.1371/journal.pone.0037414
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kwon YT
中科院分区：
文献类型：
--
作者：
An JY;Kim E;Zakrzewska A;Yoo YD;Jang JM;Han DH;Lee MJ;Seo JW;Lee YJ;Kim TY;de Rooij DG;Kim BY;Kwon YT
n端规则通路是一种蛋白质水解系统，其识别组分（n -识别蛋白）将不稳定的短寿命蛋白质的n端残基识别为特定degrons （N-degrons）的基本元素。RING E3连接酶UBR2和UBR1是主要的n -识别蛋白，它们与N-degrons共享大小（200 kDa）、保守结构域和底物特异性。尽管已知n端规则通路在胞质蛋白降解中的功能，但ubr2缺陷雄性小鼠的主要表型是由于精母细胞在减数分裂前期i期被阻滞而导致的不育。ubr2缺陷的精母细胞在性染色体相关基因的转录沉默和组蛋白H2A的泛素化中受损。在这项研究中，我们发现UBR2在减数分裂染色体上的募集在时空上与染色质相关的泛素化的诱导相关，这在缺乏UBR2的精母细胞中显著受损。UBR2作为支架E3，通过不同于典型多泛素化的机制，促进HR6B/ ubch2依赖性H2A和H2B的泛素化，而不是H3和H4的泛素化。UBR2在组蛋白泛素化中的E3活性被带有不稳定n端残基的二肽变构激活。缺乏ubr2的减数分裂染色体的单泛素化和多泛素化不足与双链断裂（DSB）修复和其他减数分裂过程中的缺陷相关，导致IV期粗线素阻滞和细胞凋亡。UBR2的一些功能在体细胞中被观察到，其中UBR2是一种染色质结合蛋白，参与DNA损伤时染色质相关的泛素化。缺乏ubr2的体细胞表现出一系列染色体异常，包括过度增殖、染色体不稳定和对DNA损伤诱导试剂的超敏反应。富含C57背景的ubr2缺陷小鼠在出生时死于肺扩张和神经发育缺陷。因此，UBR2作为一个主要的细胞蛋白水解系统的识别组分，与染色质有关，并控制生殖细胞和体细胞的染色质动力学和基因表达。
The N-end rule pathway is a proteolytic system in which its recognition components (N-recognins) recognize destabilizing N-terminal residues of short-lived proteins as an essential element of specific degrons, called N-degrons. The RING E3 ligases UBR2 and UBR1 are major N-recognins that share size (200 kDa), conserved domains and substrate specificities to N-degrons. Despite the known function of the N-end rule pathway in degradation of cytosolic proteins, the major phenotype of UBR2-deficient male mice is infertility caused by arrest of spermatocytes at meiotic prophase I. UBR2-deficient spermatocytes are impaired in transcriptional silencing of sex chromosome-linked genes and ubiquitylation of histone H2A. In this study we show that the recruitment of UBR2 to meiotic chromosomes spatiotemporally correlates to the induction of chromatin-associated ubiquitylation, which is significantly impaired in UBR2-deficient spermatocytes. UBR2 functions as a scaffold E3 that promotes HR6B/UbcH2-dependent ubiquitylation of H2A and H2B but not H3 and H4, through a mechanism distinct from typical polyubiquitylation. The E3 activity of UBR2 in histone ubiquitylation is allosterically activated by dipeptides bearing destabilizing N-terminal residues. Insufficient monoubiquitylation and polyubiquitylation on UBR2-deficient meiotic chromosomes correlate to defects in double strand break (DSB) repair and other meiotic processes, resulting in pachytene arrest at stage IV and apoptosis. Some of these functions of UBR2 are observed in somatic cells, in which UBR2 is a chromatin-binding protein involved in chromatin-associated ubiquitylation upon DNA damage. UBR2-deficient somatic cells show an array of chromosomal abnormalities, including hyperproliferation, chromosome instability, and hypersensitivity to DNA damage-inducing reagents. UBR2-deficient mice enriched in C57 background die upon birth with defects in lung expansion and neural development. Thus, UBR2, known as the recognition component of a major cellular proteolytic system, is associated with chromatin and controls chromatin dynamics and gene expression in both germ cells and somatic cells.
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DOI：
10.1073/pnas.0910267107
发表时间：
2010-02-02
影响因子：
11.1
作者：
An, Jee Young;Kim, Eun-A.;Kwon, Yong Tae
通讯作者：
Kwon, Yong Tae
影响因子：
4
作者：
Baarends, Willy M.;Wassenaar, Evelyne;Grootegoed, J. Anton
通讯作者：
Grootegoed, J. Anton
影响因子：
5.3
作者：
Baarends, WM;Wassenaar, E;Grootegoed, JA
通讯作者：
Grootegoed, JA
影响因子：
2.7
作者：
Baarends, WM;Hoogerbrugge, TW;Grootegoed, JA
通讯作者：
Grootegoed, JA
影响因子：
16
作者：
Garcia-Higuera, I;Taniguchi, T;D'Andrea, AD
通讯作者：
D'Andrea, AD