在复制叉上动态的de novo异色素组装和拆卸确保了叉的稳定性
Vincent Gaggioli1,2, Calvin S Y Lo1, Nazaret Reverón-Gómez3,4
1Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
Nature cell biology
|July 6, 2023
概括
基因复制分叉是通过形成异色染色素的基因组修饰来稳定. 这个过程涉及EHMT2/G9a和SUV39h1,影响化疗耐药性.
科学领域:
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 癌症研究 癌症研究
背景情况:
- 基因复制叉的稳定性对基因组完整性至关重要.
- 在应力复制分叉时,染色质动态的表观遗传调节仍然不太了解.
研究的目的:
- 阐明表观遗传重组在维持在压力下复制叉稳定的作用.
- 为了确定关键的分子参与者参与染色体信号在挑战复制分叉.
主要方法:
- 生物化学试验用于研究蛋白质相互作用和酶活性.
- 单分子色素纤维分析以评估色素结构.
- 细胞测试以评估对DNA复制和药物敏感性的影响.
主要成果:
- 通过检查点调节的级联激活EHMT2/G9a,导致在应力复制分叉处的异染色素组合.
- 通过H3K9me1/me2/me3积累,G9a和SUV39h1合作诱导色素紧缩.
- 通过G9a介导的JMJD1A/KDM3A的排除可以防止过早的异性染色素分解.
- 通过KDM3A的过早拆解,允许PRIMPOL访问,导致DNA缺口和对化疗药物的敏感性增加.
结论:
- 通过G9a和SUV39h1的检查点调节的异色素组合稳定了应力复制叉.
- G9a和KDM3A活动之间的平衡决定了异色染色素动态和分叉重新启动.
- 高G9a/H3K9me3水平可能导致癌症患者的化疗耐药性.
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