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研究发现神经元增强子内存在DNA单链断裂修复
2021-03-28 12:58

美国国立卫生研究院Andr Nussenzweig、Michael E. Ward和捷克科学院分子遗传研究所Keith W. Caldecott研究组合作取得一项新成果。经过不懈努力,他们发现神经元增强子是DNA单链断裂修复的热点。这一研究成果在线发表在2021年3月25日出版的国际学术期刊《自然》上。

研究人员发现有丝分裂后神经元在基因组内的特定位点产生并累积了较多的DNA单链断裂(SSB)。全基因组图谱揭示了SSB位于CpG二核苷酸或DNA脱甲基位点或附近的增强子区域。这些SSB通过PARP1和XRCC1依赖的机制修复。值得注意的是,XRCC1依赖性短程修复的缺陷会增加神经元增强子的DNA修复合成,而长程修复缺陷则会降低该合成。因此,短程和长程修复过程都可能参与神经元增强子中高水平的SSB修复。

这些数据首次提供了特定位点和细胞类型SSB修复的证据,揭示了神经元中未知的局部和连续DNA断裂。另外,研究人员认为该机制可对SSB修复缺陷患者中发生的神经变性表型进行解释。

据介绍,DNA修复缺陷经常导致神经发育和神经退行性疾病,这印证了DNA修复在有丝分裂后长寿神经元中的重要性。细胞基因组经常受到内源性DNA损伤的干扰,但是人们对神经元中积累病变的功能以及它们是否在整个基因组或特定基因座中积累了解甚少。

附:英文原文

Title: Neuronal enhancers are hotspots for DNA single-strand break repair

Author: Wei Wu, Sarah E. Hill, William J. Nathan, Jacob Paiano, Elsa Callen, Dongpeng Wang, Kenta Shinoda, Niek van Wietmarschen, Jennifer M. Coln-Mercado, Dali Zong, Raffaella De Pace, Han-Yu Shih, Steve Coon, Maia Parsadanian, Raphael Pavani, Hana Hanzlikova, Solji Park, Seol Kyoung Jung, Peter J. McHugh, Andres Canela, Chongyi Chen, Rafael Casellas, Keith W. Caldecott, Michael E. Ward, Andr Nussenzweig

Issue&Volume: 2021-03-25

Abstract: Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons1,2. The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breaks (SSBs) at specific sites within the genome. Genome-wide mapping reveals that SSBs are located within enhancers at or near CpG dinucleotides and sites of DNA demethylation. These SSBs are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair increase DNA repair synthesis at neuronal enhancers, whereas defects in long-patch repair reduce synthesis. The high levels of SSB repair in neuronal enhancers are therefore likely to be sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell type-specific SSB repair, revealing unexpected levels of localized and continuous DNA breakage in neurons. In addition, they suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.

DOI: 10.1038/s41586-021-03468-5

Source: https://www.nature.com/articles/s41586-021-03468-5

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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