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反复出现的 DNA 缺口导致（GAA）重复序列的大量扩增。

Recurrent DNA nicks drive massive expansions of (GAA) repeats.

机构信息

Department of Biology, Tufts University, Medford, MA 02155.

出版信息

Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2413298121. doi: 10.1073/pnas.2413298121. Epub 2024 Nov 25.

DOI:10.1073/pnas.2413298121
PMID:39585990
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11626148/
Abstract

Over 50 hereditary degenerative disorders are caused by expansions of short tandem DNA repeats (STRs). (GAA) repeat expansions are responsible for Friedreich's ataxia as well as late-onset cerebellar ataxias (LOCAs). Thus, the mechanisms of (GAA) repeat expansions attract broad scientific attention. To investigate the role of DNA nicks in this process, we utilized a CRISPR-Cas9 nickase system to introduce targeted nicks adjacent to the (GAA) repeat tract. We found that DNA nicks 5' of the (GAA) run led to a dramatic increase in both the rate and scale of its expansion in dividing cells. Strikingly, they also promoted large-scale expansions of carrier- and large normal-size (GAA) repeats, recreating, in a model system, the expansion events that occur in human pedigrees. DNA nicks 3' of the (GAA) repeat led to a smaller but significant increase in the expansion rate as well. Our genetic analysis implies that in dividing cells, conversion of nicks into double-strand breaks (DSBs) during DNA replication followed by DSB or fork repair leads to repeat expansions. Finally, we showed that 5' GAA-strand nicks increase expansion frequency in nondividing yeast cells, albeit to a lesser extent than in dividing cells.

摘要

超过 50 种遗传性退行性疾病是由短串联 DNA 重复序列 (STRs) 的扩展引起的。(GAA) 重复扩展负责弗里德里希共济失调以及晚发性小脑共济失调 (LOCAs)。因此，(GAA) 重复扩展的机制引起了广泛的科学关注。为了研究 DNA 切口在这个过程中的作用，我们利用 CRISPR-Cas9 切口酶系统在 (GAA) 重复序列附近引入靶向切口。我们发现 (GAA) 运行 5' 的 DNA 切口导致其在分裂细胞中的扩展速度和规模显著增加。引人注目的是，它们还促进了携带者和大正常大小 (GAA) 重复的大规模扩展，在模型系统中重现了发生在人类家系中的扩展事件。(GAA) 重复 3' 的 DNA 切口也导致扩展速度略有但显著增加。我们的遗传分析表明，在分裂细胞中，DNA 复制过程中切口转化为双链断裂 (DSB)，随后 DSB 或叉修复导致重复扩展。最后，我们表明 5' GAA 链切口增加了非分裂酵母细胞中的扩展频率，尽管程度低于分裂细胞。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/7afbe1dbc033/pnas.2413298121fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/0582951ca1e2/pnas.2413298121fig01.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/920de6b54fcd/pnas.2413298121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/b7b5973cb2df/pnas.2413298121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/7b3c6edd1c26/pnas.2413298121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/86c1942ae248/pnas.2413298121fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/7afbe1dbc033/pnas.2413298121fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/0582951ca1e2/pnas.2413298121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/1d89288fe1ba/pnas.2413298121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/442c9003883e/pnas.2413298121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/920de6b54fcd/pnas.2413298121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/b7b5973cb2df/pnas.2413298121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/7b3c6edd1c26/pnas.2413298121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/86c1942ae248/pnas.2413298121fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e00e/11626148/7afbe1dbc033/pnas.2413298121fig08.jpg

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