UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination

被引:65
作者
An, Jee Young [1 ,2 ]
Kim, Eun-A. [1 ,2 ]
Jiang, Yonghua [1 ,2 ]
Zakrzewska, Adriana [1 ,2 ]
Kim, Dong Eun [1 ,2 ]
Lee, Min Jae [3 ]
Mook-Jung, Inhee [4 ]
Zhang, Yi [5 ]
Kwon, Yong Tae [1 ,2 ]
机构
[1] Univ Pittsburgh, Sch Pharm, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA
[3] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[4] Seoul Natl Univ, Coll Med, Dept Biochem & Biomed Sci, Seoul 110799, South Korea
[5] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA
基金
美国国家卫生研究院; 新加坡国家研究基金会;
关键词
chromatin inactivation; H2A; meiosis; N-end rule; ubiquitin; H2A UBIQUITINATION; MICE LACKING; XY BODY; LIGASE; UBIQUITYLATION; MONOUBIQUITINATION; PHOSPHORYLATION; CHROMATIN; MOUSE;
D O I
10.1073/pnas.0910267107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:1912 / 1917
页数:6
相关论文
共 25 条
[1]   Impaired neurogenesis and cardiovascular development in mice lacking the E3 ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway [J].
An, JY ;
Seo, JW ;
Tasaki, T ;
Lee, MJ ;
Varshavsky, A ;
Kwon, YT .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (16) :6212-6217
[2]   Increased phosphorylation and dimethylation of XY body histones in the Hr6b-knockout mouse is associated with derepression of the X chromosome [J].
Baarends, Willy M. ;
Wassenaar, Evelyne ;
Hoogerbrugge, Jos W. ;
Schoenmakers, Sam ;
Sun, Zu-Wen ;
Grootegoed, J. Anton .
JOURNAL OF CELL SCIENCE, 2007, 120 (11) :1841-1851
[3]   Silencing of unpaired chromatin and histone H2A ubiquitination in mammalian meiosis [J].
Baarends, WM ;
Wassenaar, E ;
van der Laan, R ;
Hoogerbrugge, J ;
Sleddens-Linkels, E ;
Hoeijmakers, JHJ ;
de Boer, P ;
Grootegoed, JA .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (03) :1041-1053
[4]   INVIVO HALF-LIFE OF A PROTEIN IS A FUNCTION OF ITS AMINO-TERMINAL RESIDUE [J].
BACHMAIR, A ;
FINLEY, D ;
VARSHAVSKY, A .
SCIENCE, 1986, 234 (4773) :179-186
[5]   Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing [J].
Cao, R ;
Tsukada, Y ;
Zhang, Y .
MOLECULAR CELL, 2005, 20 (06) :845-854
[6]   Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation [J].
de Napoles, M ;
Mermoud, JE ;
Wakao, R ;
Tang, YA ;
Endoh, M ;
Appanah, R ;
Nesterova, TB ;
Silva, J ;
Otte, AP ;
Vidal, M ;
Koseki, H ;
Brockdorff, N .
DEVELOPMENTAL CELL, 2004, 7 (05) :663-676
[7]   Ring1b-mediated H2A ubiquitination associates with inactive X chromosomes and is involved in initiation of X inactivation [J].
Fang, J ;
Chen, TP ;
Chadwick, B ;
Li, E ;
Zhang, Y .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (51) :52812-52815
[8]  
HAAS AL, 1988, J BIOL CHEM, V263, P13268
[9]   RAD6-Mediated Transcription-Coupled H2B Ubiquitylation Directly Stimulates H3K4 Methylation in Human Cells [J].
Kim, Jaehoon ;
Guermah, Mohamed ;
McGinty, Robert K. ;
Lee, Jung-Shin ;
Tang, Zhanyun ;
Milne, Thomas A. ;
Shilatifard, Ali ;
Muir, Tom W. ;
Roeder, Robert G. .
CELL, 2009, 137 (03) :459-471
[10]   Female lethality and apoptosis of spermatocytes in mice lacking the UBR2 ubiquitin ligase of the N-end rule pathway [J].
Kwon, YT ;
Xia, ZX ;
An, JY ;
Tasaki, T ;
Davydov, IV ;
Seo, JW ;
Sheng, J ;
Xie, YM ;
Varshavsky, A .
MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (22) :8255-8271