Genomic instability in laminopathy-based premature aging
Genomic instability in laminopathy-based premature aging
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DOI：
10.1038/nm1266
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发表时间：
2005-07-01
期刊：
影响因子：
82.9
通讯作者：
Zhou, ZJ
中科院分区：
文献类型：
--
作者：
Liu, BH;Wang, JM;Zhou, ZJ
早衰综合征通常是由参与维持基因组完整性的核蛋白突变引起的。核纤层蛋白A是核纤层和核骨架的主要成分。核纤层蛋白A的截断导致Hutchinson-Gilford早老综合征（HGPS），一种严重的早发性早衰。缺乏功能性Zmpste 24，一种负责层蛋白前体A成熟的金属蛋白酶，也会导致小鼠和人类的早衰症表型。我们发现Zmpste 24缺陷小鼠胚胎成纤维细胞（MEFs）显示出增加的DNA损伤和染色体畸变，对DNA损伤剂更敏感。从Zmpste 24（-/-）小鼠分离的骨髓细胞显示出增加的非整倍性，并且小鼠对DNA损伤剂更敏感。在Zmpste 24（-/-）MEFs和HGPS成纤维细胞中，p53结合蛋白1（53 BP 1）和Rad 51向DNA损伤位点的募集受损，导致检查点反应延迟和DNA修复缺陷。异位表达不可加工的前层蛋白A的野生型MEFs在检查点反应和DNA修复中显示出类似的缺陷。我们的研究结果表明，未加工的prelamin A和截短的lamin A的行为显性负干扰DNA损伤的反应和修复，导致基因组的不稳定性，这可能有助于基于laminopathy的过早衰老。
Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. Lamin A is a major component of the nuclear lamina and nuclear skeleton. Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging. Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24(-/-) mice show increased aneuploidy and the mice are more sensitive to DNA- damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesion is impaired in Zmpste24(-/-) MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging.