Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
DNA Repair (Amst). 2023 Oct;130:103549. doi: 10.1016/j.dnarep.2023.103549. Epub 2023 Aug 3.
DNA damages compromise cell function and fate. Cells of all organisms activate a global DNA damage response that includes a signaling stress response, activation of checkpoints, and recruitment of repair enzymes. Especially deleterious are bulky, helix-distorting damages that block transcription and replication. Due to their miscoding nature, these damages lead to mutations and cancer. In human cells, bulky DNA damages are repaired by nucleotide excision repair (NER). To date, the basic mechanism of NER in naked DNA is well defined. Still, there is a fundamental gap in our understanding of how repair is orchestrated despite the packaging of DNA in chromatin, and how it is coordinated with active transcription and replication. The last decade has brought forth huge advances in our ability to detect and assay bulky DNA damages and their repair at single nucleotide resolution across the human genome. Here we review recent findings on the effect of chromatin and DNA-binding proteins on the formation of bulky DNA damages, and novel insights on NER, provided by the recent application of genomic methods.
DNA 损伤会损害细胞功能和命运。所有生物体的细胞都会激活一种全局性的 DNA 损伤反应，其中包括信号应激反应、检测点激活以及修复酶的募集。特别有害的是体积大、扭曲双螺旋的损伤，这些损伤会阻碍转录和复制。由于其致错性质，这些损伤会导致突变和癌症。在人类细胞中，体积大的 DNA 损伤由核苷酸切除修复（NER）修复。迄今为止，裸 DNA 中 NER 的基本机制已经得到很好的定义。然而，尽管 DNA 被包装在染色质中，我们对修复是如何协调的，以及它如何与活跃的转录和复制相协调，仍然存在根本的理解差距。在过去的十年中，我们在检测和分析人类基因组中单核苷酸分辨率下的大体积 DNA 损伤及其修复方面的能力取得了巨大的进展。在这里，我们回顾了最近关于染色质和 DNA 结合蛋白对大体积 DNA 损伤形成的影响的发现，以及基因组学方法最近应用提供的关于 NER 的新见解。
