Watanabe Reiko, Kanno Shin-Ichiro, Mohammadi Roushandeh Amaneh, Ui Ayako, Yasui Akira
Division of Dynamic Proteome and IDAC Fellow Research Group for DNA Repair and Dynamic Proteome Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai 980-8575, Japan.
Division of Dynamic Proteome and IDAC Fellow Research Group for DNA Repair and Dynamic Proteome Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai 980-8575, Japan
Philos Trans R Soc Lond B Biol Sci. 2017 Oct 5;372(1731). doi: 10.1098/rstb.2016.0473.
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'.
核小体重塑（NR）以ATP依赖的方式调节转录，并影响发育和细胞功能所需的基因表达，包括那些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）和与Brahma相关的因子（BAF）复合物，分别属于ISWI和SWI/SNF家族，参与各种类型的DNA修复。抑制几种BAF因子会使U2OS细胞对X射线、紫外线尤其是顺铂显著敏感，并且这些BAF因子有助于修复蛋白在各种类型的DNA损伤处积累以及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发生突变，或者更常见的是沉默。因此，那些癌细胞可能对X射线尤其是顺铂敏感，这提示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会影响干细胞功能，导致细胞衰老。BAF因子的遗传和表观遗传变化会削弱DNA修复以及转录调控活性，而DNA修复缺陷反过来又会对NR和转录调控产生负面影响。因此，它们形成负反馈回路，分别作为常见和罕见的细胞事件加速细胞衰老和转化，从而导致细胞老化。
本文是主题为“DNA修复和信号传导中的染色质修饰剂和重塑剂”的特刊的一部分。
