Lamin A Δexon9 mutation leads to telomere and chromatin defects but not genomic instability
Lamin A Δexon9 mutation leads to telomere and chromatin defects but not genomic instability
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DOI：
10.4161/nucl.26873
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发表时间：
2013-09-01
期刊：
影响因子：
3.7
通讯作者：
Gonzalo, Susana
中科院分区：
文献类型：
--
作者：
Das, Arindam;Grotsky, David A.;Gonzalo, Susana
编码A型核纤层蛋白的LMNA基因中的300多个突变与15种人类退行性疾病和早衰综合征相关。虽然基因组的不稳定性似乎有助于某些核纤层蛋白病的病理生理学，但关于什么样的突变导致基因组不稳定性以及通过什么样的分子机制的信息有限。缺失A型核纤层蛋白或表达缺失外显子8-11的突变体（Lmna（Delta 8-11/Delta 8-11））的小鼠胚胎成纤维细胞表现出端粒生物学和DNA修复的改变，这是由组织蛋白酶L介导的53 BP 1降解和BRCA 1和RAD 51表达减少引起的。因此，包含外显子8-11的区域似乎对基因组完整性至关重要。鉴于小鼠核纤层蛋白A外显子9的缺失（Lmna（Delta 9/Delta 9））导致早衰表型，我们测试了该结构域是否对基因组完整性重要。Lmna（Delta 9/Delta 9）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53 BP 1降解，并维持BRCA 1和RAD 51的表达。因此，Lmna（Delta 9/Delta 9）MEF不存在基因组不稳定性，并且突变体核纤层蛋白A Delta外显子9在核纤层蛋白耗尽的细胞中的表达恢复DNA修复因子水平并部分挽救核异常。这些数据表明，由外显子9编码的结构域对于维持端粒稳态和异染色质结构是重要的，但在DNA修复中不起作用，因此指出核纤层蛋白A尾部中的其他外显子是Lmna（Delta 8-11/Delta 8-11）小鼠中基因组不稳定表型的原因。我们的研究还表明，DNA修复因子53 BP 1，BRCA 1和RAD 51的水平可能作为生物标志物，以识别存在基因组不稳定性的核纤层蛋白病。
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(Delta 8-11/Delta 8-11)) 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(Delta 9/Delta 9)) results in a progeria phenotype, we tested if this domain is important for genome integrity. Lmna(Delta 9/Delta 9) 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(Delta 9/Delta 9) MEFs do not present genomic instability, and expression of mutant lamin A Delta exon9 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(Delta 8-11/Delta 8-11) 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.