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首页> 外文期刊>Nucleus >Lamin A Δexon9 mutation leads to telomere and chromatin defects but not genomic instability
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Lamin A Δexon9 mutation leads to telomere and chromatin defects but not genomic instability

机译：Lamin AΔexon9突变导致端粒和染色质缺陷，但不会导致基因组不稳定

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Over 300 mutations in the LMNA gene, encoding A-type lamins, are associated with 15 human degenerative disorders and premature aging syndromes. Although genomic instability seems to contribute to the pathophysiology of some laminopathies, there is limited information about what mutations cause genomic instability and by which molecular mechanisms. Mouse embryonic fibroblasts depleted of A-type lamins or expressing mutants lacking exons 8–11 (Lmna~(Δ8–11/Δ8–11) ) exhibit alterations in telomere biology and DNA repair caused by cathepsin L-mediated degradation of 53BP1 and reduced expression of BRCA1 and RAD51. Thus, a region encompassing exons 8–11 seems essential for genome integrity. Given that deletion of lamin A exon 9 in the mouse (Lmna~(Δ9/Δ9) ) results in a progeria phenotype, we tested if this domain is important for genome integrity. Lmna~(Δ9/Δ9) MEFs exhibit telomere shortening and heterochromatin alterations but do not activate cathepsin L-mediated degradation of 53BP1 and maintain expression of BRCA1 and RAD51. Accordingly, Lmna~(Δ9/Δ9) MEFs do not present genomic instability, and expression of mutant lamin A Δexon9 in lamin-depleted cells restores DNA repair factors levels and partially rescues nuclear abnormalities. These data reveal that the domain encoded by exon 9 is important to maintain telomere homeostasis and heterochromatin structure but does not play a role in DNA repair, thus pointing to other exons in the lamin A tail as responsible for the genomic instability phenotype in Lmna~(Δ8–11/Δ8–11) mice. Our study also suggests that the levels of DNA repair factors 53BP1, BRCA1 and RAD51 could potentially serve as biomarkers to identify laminopathies that present with genomic instability.
机译：LMNA基因中编码A型lamins的300多个突变与15种人类退化性疾病和早衰综合症有关。尽管基因组不稳定似乎有助于某些拉丁病的病理生理，但关于哪些突变导致基因组不稳定以及通过哪些分子机制的信息仍然有限。小鼠胚胎成纤维细胞中缺乏A型层纤层蛋白或表达缺乏外显子8-11（ Lmna〜（Δ8-11/Δ8-11））的突变体，其表现出由组织蛋白酶L介导的53BP1降解引起的端粒生物学和DNA修复并降低了BRCA1和RAD51的表达。因此，一个包含第8-11号外显子的区域似乎对于基因组完整性至关重要。考虑到小鼠中lamin A外显子9的缺失（Lmna〜（Δ9/Δ9））导致早衰表型，我们测试了该结构域对基因组完整性是否重要。 Lmna〜（Δ9/Δ9）MEFs表现出端粒缩短和异染色质改变，但不激活组织蛋白酶L介导的53BP1降解并维持BRCA1和RAD51的表达。因此，Lmna〜（Δ9/Δ9）MEFs不存在基因组不稳定性，并且在薄层细胞耗尽的细胞中表达突变型薄层蛋白AΔexon9的表达恢复了DNA修复因子的水平，并部分挽救了核异常。这些数据表明，外显子9编码的结构域对于维持端粒稳态和异染色质结构很重要，但在DNA修复中不起作用，因此指出层纤体A尾巴中的其他外显子是导致基因组不稳定表型的原因。 Lmna〜（Δ8-11/Δ8-11）小鼠。我们的研究还表明，DNA修复因子53BP1，BRCA1和RAD51的水平可以潜在地用作生物标志物，以鉴定出基因组不稳定的拉丁病。

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