组织素H2A氨酸119的结构基础是通过Polycomb抑制性二维基因酶BAP1/ASXL1的二维基因化
Jonathan F Thomas1, Marco Igor Valencia-Sánchez1, Simone Tamburri2,3
1Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA.
Science advances
|August 9, 2023
概括
在Polycomb抑制二维基因酶复合体 (PR-DUB) 删除组蛋白H2AK119Ub调节基因表达. 这项研究揭示了PR-DUB的结构和H2AK119Ub特异性的机制,解释了癌症突变如何影响其功能.
科学领域:
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 基因组H2A氨酸119单双化 (H2AK119Ub) 是由波利康布抑制复合体1和波利康布抑制双化酶复合体 (PR-DUB) 调节的.
- PR-DUB活动对于保持活跃的基因表达和防止异常沉默至关重要.
- 在人类癌症中,PR-DUB子单元BAP1和ASXL1的突变很常见,但它们的功能影响仍然不清楚.
研究的目的:
- 阐明PR-DUB为H2AK119Ub.Ub.确定特异性的分子机制.
- 了解BAP1和ASXL1癌症相关突变如何影响PR-DUB活动.
- 提供关于PR-DUB与H2AK119Ub核素的相互作用的结构见解.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定人类BAP1-ASXL1 DEUBAD复合体与H2AK119Ub核素的结构.
- 生物化学测试以评估脱活动.
- 细胞研究,以调查突变的功能后果.
主要成果:
- 确定了BAP1-ASXL1 DEUBAD复合体与H2AK119Ub核细胞组结合的冷EM结构.
- 确定了BAP1,ASXL1,基因素和DNA之间的关键分子相互作用,这些相互作用为H2AK119Ub.赋予了特异性.
- 证明了BAP1和ASXL1中的50多个与癌症相关的突变如何破坏H2AK119Ub的二氧化化.
结论:
- PR-DUB利用特定的相互作用来识别和重组H2AK119Ub核酶体,从而建立了deubiquitination的特异性.
- BAP1和ASXL1中的癌症突变损害了PR-DUB功能,为癌症病因学提供了分子洞察力.
- 对PR-DUB的结构和功能理解为针对癌症表观遗传失调的治疗策略提供了基础.
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