Characterization of premature liver polyploidy in DNA repair (Ercc1)-deficient mice
Characterization of premature liver polyploidy in DNA repair (Ercc1)-deficient mice
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DOI：
10.1053/jhep.2003.50421
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发表时间：
2003-10-01
期刊：
影响因子：
13.5
通讯作者：
Melton, DW
中科院分区：
文献类型：
--
作者：
Chipchase, MD;O'Neill, M;Melton, DW
ERCC1-XPF是核苷酸切除修复（NER）中切割5'损伤的内切酶。与其他NER蛋白不同，ERCC1-XPF也参与DNA链间交联的重组和修复。独特的NER基因敲除，Ercc1缺失小鼠严重矮胖与高水平的肝细胞多倍体。为了了解DNA修复缺陷与多倍体之间的联系，我们将Ercc1缺失肝脏的过早多倍体与衰老对照小鼠多倍体的正常发育进行了比较。在Ercc1缺失的肝细胞中，多倍性显著加速，因此在3周龄的Ercc1缺失小鼠和1至2岁的野生型小鼠肝脏中，倍性水平相当。细胞周期蛋白依赖性激酶抑制剂p21的水平在Ercc1缺失的肝细胞中升高，这种升高集中在多倍体肝细胞中，但不限于多倍体肝细胞。在相同倍性水平的老野生型肝脏中发现了更低水平的p21信使RNA （mRNA）。我们认为，Ercc1缺失的肝脏中DNA损伤的更快积累导致p21水平的增加，但p21之间没有简单的直接联系。水平和过早多倍体。在衰老的野生型肝脏中，未能观察到p21水平与多倍体之间的任何联系，可能是由于累积的DNA损伤水平低得多，涉及的时间尺度大得多，或者存在不依赖于p21的多倍体机制。总之，ercc1缺陷肝脏的过早多倍体不同于正常的衰老相关过程。
ERCC1-XPF is the endonuclease that cuts 5' of the damage in nucleotide excision repair (NER). Unlike other NER proteins, ERCC1-XPF is also involved in recombination and the repair of DNA interstrand cross-links. Unique among the NER gene knockouts, Ercc1 null mice are severely runted with high levels of hepatocyte polyploidy. To understand the link between DNA repair deficiency and polyploidy we have compared the premature polyploidy in Ercc1 null liver with the normal development of polyploidy in aging control mice. Polyploidy was accelerated dramatically in Ercc1 null hepatocytes, such that ploidy levels were equivalent in 3-week-old Ercc1 null and 1- to 2-year-old wild-type mouse liver. Levels of the cyclin-dependent kinase inhibitor, p21, were increased in the nuclei of Ercc1 null hepatocytes, and this increase was concentrated in, but not confined to, the polyploid hepatocytes. Much lower levels of p21 messenger RNA (mRNA) were found in old wild-type liver with equivalent levels of ploidy. We suggest that the more rapid accumulation of DNA damage in Ercc1 null liver leads to an increase in p21 levels, but that there is not a simple direct link between p21. levels and premature polyploidy. The failure to observe any link between p21 levels and polyploidy in aged wild-type liver may be attributable to the much lower levels of accumulated DNA damage, the much greater timescale involved, or the existence of a p21-independent mechanism for polyploidy. In conclusion, the premature polyploidy in Ercc1-deficient liver differs from the normal aging-related process.