HSCARG, a novel regulator of H2A ubiquitination by downregulating PRC1 ubiquitin E3 ligase activity, is essential for cell proliferation.
Histone H2A ubiquitination plays critical roles in transcriptional repression and deoxyribonucleic acid (DNA) damage response. More attention has been focused on ubiquitin E3 ligases of H2A, however, less is known about the negative regulators of H2A ubiquitination. Here we identified HSCARG as a new negative regulatory protein for H2A ubiquitination and found a possible link between regulator of H2A ubiquitination and cell cycle. Mechanistically, HSCARG interacts with polycomb repressive complex 1 (PRC1) and deubiquitinase USP7 and inhibits PRC1 ubiquitination in a USP7-dependent manner. As ubiquitination of PRC1 is critical for its E3 ligase activity toward H2A, HSCARG and USP7 are further shown to decrease the level of H2A ubiquitination. Moreover, we demonstrated that HSCARG is involved in DNA damage response through affecting the level of H2A ubiquitination and localization of RAP80 at lesion points. Knockout of HSCARG results in persistent activation of checkpoint signaling and leads to cell cycle arrest. This study unravels a novel mechanism for the regulation of H2A ubiquitination and elucidates how regulators of H2A ubiquitination affect cell cycle.
State Key Lab of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China.
Bin
B
Hu
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Shangze
S
Li
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Xiaodong
X
Zhang
State Key Lab of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China xiaofengz@pku.edu.cn.
Xiaofeng
X
Zheng
D002352:Carrier Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D056488:Histone Chaperones; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D006657:Histones; C520476:NMRAL1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; C466234:UIMC1 protein, human; D063150:Polycomb Repressive Complex 1; C080355:RING1 protein, human; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7