在DNA断裂处的非对称核细胞体PARylation介导着ALC1的定向核细胞体滑动
Luka Bacic1, Guillaume Gaullier1,2, Jugal Mohapatra3
1Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 75124, Uppsala, Sweden.
Nature communications
|February 2, 2024
概括
染色体重塑剂ALC1被多ADP-ribose招募到DNA损伤部位,并指导核细胞从断裂中滑走. 这种机制有助于DNA修复因子的可访问性.
科学领域:
- 分子生物学分子生物学
- 生物化学 生物化学
- 结构生物学 结构生物学
背景情况:
- 染色体重塑剂ALC1通过在DNA损伤时由PARP1/PARP2和HPF1产生的多ADP-ribose (PAR) 链被激活.
- ALC1是一个有前途的癌症药物标,但其精确的招募机制到ADP-ribosylated核细胞和随后的核细胞在DNA断裂附近的定位仍然不清楚.
研究的目的:
- 阐明ALC1招募到ADP-ribosylated核细胞体中的机制及其在DNA断裂附近核细胞体定位中的作用.
主要方法:
- 在基因素H2B尾部产生具有不对称ADP-ribosylation的核体.
- 低温电子显微镜 (cryo-EM) 用于确定ALC1与不对称核体结合的结构.
- 单分子福斯特共振能量转移 (smFRET) 用于研究核细胞的滑动动力学.
主要成果:
- PARP1/HPF1首选在接近DNA断裂的基因素H2B尾部上启动ADP-ribosylation.
- 冷-EM结构显示ALC1优先与不对称的ADP-ribosylated核酶体进行接触.
- smFRET实验表明,不对称的ALC1招募导致导向核细胞从ADP-ribosylation位点滑开.
结论:
- ALC1被非对称地招募到ADP-ribosylated核细胞体中,由PAR链在基因素H2B上的位置驱动.
- 这种不对称的招募触发了指导核细胞体滑动,使核细胞体远离DNA断裂.
- 通过ALC1介导的核细胞重新定位使得DNA断裂更容易被用于修复机械,突出了DNA损伤反应的关键步骤.
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