Yeast Nhp6A/B and mammalian Hmgb1 facilitate the maintenance of genome stability
Yeast Nhp6A/B and mammalian Hmgb1 facilitate the maintenance of genome stability
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DOI：
10.1016/j.cub.2004.12.065
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发表时间：
2005-01-11
期刊：
影响因子：
9.2
通讯作者：
Jackson, SP
中科院分区：
文献类型：
--
作者：
Giavara, S;Kosmidou, E;Jackson, SP
酿酒酵母Nhp6A和Nhp6B是高迁移率族盒(HMGB)超家族的染色质结构因子，在功能上与哺乳动物HMGB1相关[1]。它们以非序列特异性的方式结合到双链DNA的小凹槽上，从而影响染色质结构[3]。以前的工作涉及到这些蛋白质参与多种核过程，包括染色质重塑、DNA复制、转录和重组[4-10]。在这里，我们表明Nhp6A/B的丢失会导致基因组的不稳定性增加，对DNA损伤剂的超敏反应，以及与染色体外rDNA环水平升高相关的酵母细胞寿命缩短。此外，我们表明，对紫外线的超敏似乎并不反映DNA修复能力的下降，而是与缺乏Nhp6A/B的细胞中形成更高水平的紫外线诱导的胸腺嘧啶二聚体加合物有关。同样，我们发现缺乏HMGB1的小鼠成纤维细胞在紫外线照射后表现出比野生型对照更高的损伤率，并且也表现出明显的染色体不稳定性。综上所述，这些数据表明Nhp6A/B和HMGB1保护DNA免受损伤剂的伤害，从而防止基因组异常的产生。
Saccharomyces cerevisiae Nhp6A and Nhp6B are chromatin architectural factors that belong to the high-mobility group box (HMGB) superfamily and appear to be functionally related to mammalian Hmgb1 [1]. They bind to the minor groove of double-stranded DNA in a non-sequence-specific manner [2] and thereby influence chromatin structure [3]. Previous work has implicated these proteins in a variety of nuclear processes, including chromatin remodeling, DNA replication, transcription, and recombination [4-10]. Here, we show that Nhp6A/B loss leads to increased genomic instability, hypersensitivity to DNA-damaging agents, and shortened yeast cell life span that is associated with elevated levels of extrachromosomal rDNA circles. Furthermore, we show that hypersensitivity toward UV light does not appear to reflect a decreased capacity for DNA repair but instead correlates with higher levels of UV-induced thymine dimer adducts being formed in cells lacking Nhp6A/B. Likewise, we show that mouse fibroblasts lacking Hmgb1 display higher rates of damage after UV irradiation than wild-type controls and also exhibit pronounced chromosomal instability. Taken together, these data indicate that Nhp6A/B and Hmgb1 protect DNA from damaging agents and thus guard against the generation of genomic aberrations.