Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing
Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing
复制标题
DOI：
10.1098/rstb.2016.0473
复制
发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Reiko Watanabe;S. Kanno;Amaneh Mohammadi Roushandeh;A. Ui;A. Yasui
中科院分区：
文献类型：
--
作者：
Reiko Watanabe;S. Kanno;Amaneh Mohammadi Roushandeh;A. Ui;A. Yasui
核小体重塑（NR）以ATP依赖性方式调节转录，并影响发育和细胞功能所需的基因表达，包括参与抗癌和抗衰老过程的基因表达。利用ATP的染色质组装和重塑因子（ACF）和梵天相关因子（BAF）复合物，分别属于ISWI和SWI/SNF家族，参与各种类型的DNA修复。几种BAF因子的抑制使得U2 OS细胞对X射线、UV尤其是顺铂显著敏感，并且这些BAF因子有助于在各种类型的DNA损伤时积累修复蛋白并有助于DNA修复。最近的癌症基因组测序和表达分析表明，BAF因子在各种类型的癌细胞中经常突变，或者更经常地沉默。因此，这些癌细胞可能对X射线敏感，尤其是对顺铂敏感，这表明了一种优化当前癌症治疗的方法。最近的单干细胞分析表明，突变和表观遗传变化影响干细胞功能，导致细胞老化。BAF因子的遗传和表观遗传变化减少了DNA修复以及转录调节活性，DNA修复缺陷反过来又对NR和转录调节产生负面影响。因此，它们建立了负反馈回路，分别加速细胞衰老和转化为常见和罕见的细胞事件，导致细胞老化。这篇文章是主题问题“染色质修饰剂和重塑DNA修复和信号”的一部分。
Nucleosome remodelling (NR) regulates transcription in an ATP-dependent manner, and influences gene expression required for development and cellular functions, including those involved in anti-cancer and anti-ageing processes. ATP-utilizing chromatin assembly and remodelling factor (ACF) and Brahma-associated factor (BAF) complexes, belonging to the ISWI and SWI/SNF families, respectively, are involved in various types of DNA repair. Suppression of several BAF factors makes U2OS cells significantly sensitive to X-rays, UV and especially to cisplatin, and these BAF factors contribute to the accumulation of repair proteins at various types of DNA damage and to DNA repair. Recent cancer genome sequencing and expression analysis has shown that BAF factors are frequently mutated or, more frequently, silenced in various types of cancer cells. Thus, those cancer cells are potentially X-ray- and especially cisplatin-sensitive, suggesting a way of optimizing current cancer therapy. Recent single–stem cell analysis suggests that mutations and epigenetic changes influence stem cell functionality leading to cellular ageing. Genetic and epigenetic changes in the BAF factors diminish DNA repair as well as transcriptional regulation activities, and DNA repair defects in turn negatively influence NR and transcriptional regulation. Thus, they build negative feedback loops, which accelerate both cellular senescence and transformation as common and rare cellular events, respectively, causing cellular ageing. This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.