在BRCA缺乏的细胞中,复制叉稳定性赋予化学抵抗力
Arnab Ray Chaudhuri1, Elsa Callen1, Xia Ding2
1Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature
|July 23, 2016
概括
通过防止复制分叉降解,PTIP蛋白的损失可以保护缺乏Brca1/ 2基因的癌细胞免受DNA损伤. 这一发现为对抗化疗药物如西斯和PARP抑制剂的抗药机制提供了新的见解.
科学领域:
- 分子生物学
- 癌症研究
- 遗传学
背景情况:
- 缺少Brca1和Brca2基因的细胞表现出DNA双链断裂的同源重组修复受损.
- 这种缺陷导致对破坏DNA的药物过敏,例如西斯普拉丁和多基酶 (PARP) 抑制剂.
研究的目的:
- 研究PTIP (MLL3/4复合体中的一种蛋白质) 在Brca1/2缺乏细胞中的保护作用.
- 阐明 PTIP 缺乏导致对 DNA 破坏性物质耐药性的潜在机制.
主要方法:
- 具有或没有PTIP的Brca1/2缺乏细胞的分析.
- 在DNA双链断裂时对同类重组活性进行评估.
- 调查MRE11核酶招募到停滞的复制分叉.
- 对新生DNA链的降解进行评估.
- 在 Brca2 缺乏的瘤细胞中研究药物耐药性.
主要成果:
- 失去PTIP可以保护brca1/ 2缺乏的细胞免受DNA损伤,并挽救brca2缺乏的胚胎干细胞的致命性.
- PTIP 缺陷不会恢复同源重组,但会抑制 MRE11 加入停滞的复制分叉.
- 抑制MRE11招募可以保护新生DNA链免受降解,从而产生耐药性.
- 在 Brca2 缺乏的瘤细胞中,复制分叉保护与对 PARP 抑制剂和青的耐药性有关.
结论:
- 通过复制分叉保护,而不是同源重组修复,PTIP在保护Brca1/ 2缺乏细胞免受DNA损伤方面发挥着至关重要的作用.
- 在 Brca2 缺乏的瘤中,可以通过复制分叉保护机制获得对化疗剂的耐药性.
- 包括PARP1和CHD4在内的各种蛋白质的破坏汇聚在复制叉保护上,突出显示复杂的药物耐药性途径.
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