SETD1A的非催化功能调节林K和DNA损伤反应
Takayuki Hoshii1, Paolo Cifani2, Zhaohui Feng1
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02210, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell
|February 24, 2018
概括
在SETD1A蛋白
科学领域:
- 分子生物学
- 癌症研究
- 表观遗传学
背景情况:
- 在发育和癌症中,MLL/SET甲基转移酶对基因组甲基化至关重要.
- 一种MLL/ SET蛋白质SETD1A对于急性髓性白血病 (AML) 细胞存活至关重要.
研究的目的:
- 研究SETD1A在AML细胞存活中的作用.
- 确定SETD1A的功能领域对AML至关重要.
- 探索SETD1A影响癌细胞命运的机制.
主要方法:
- 变异性研究
- 在CRISPR-Cas9领域进行选
- 对DNA损伤反应和亡途径的分析
- 蛋白与蛋白相互作用的评估 (SETD1A和cyclin K)
主要成果:
- 对于AML细胞的存活,SETD1A的酶SET域是不可缺少的.
- 在SETD1A中的新型"FLOS"域对于AML细胞的存活至关重要.
- FLOS域中断损害了DNA损伤反应基因并触发了p53依赖的亡.
- 在S阶段,FLOS域结合于环林K,促进其染色体招募和DNA修复基因表达.
结论:
- 在AML存活中SETD1A的作用独立于它的基因组甲基转移酶活性.
- 在AML的DNA修复和细胞存活方面,FLOS域与环素K的相互作用至关重要.
- 针对SETD1A和cyclin K复合体是AML和其他癌症的潜在治疗策略.
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