Loss of rereplication control in Saccharomyces cerevisiae results in extensive DNA damage
Loss of rereplication control in Saccharomyces cerevisiae results in extensive DNA damage
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DOI：
10.1091/mbc.e04-09-0833
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发表时间：
2005-01-01
影响因子：
3.3
通讯作者：
Li, JJ
中科院分区：
文献类型：
--
作者：
Green, BM;Li, JJ
为了维持基因组的稳定性，真核细胞的整个基因组必须在每个细胞周期内复制一次且仅复制一次。在许多生物体中，多个重叠的机制阻碍了复制，但对这些机制解除管制的后果知之甚少。在这里，我们表明，破坏这些控制在萌芽酵母酿酒酵母迅速阻断细胞增殖。复制细胞激活经典的DNA损伤诱导的检查点反应，这取决于BRCA1 c端检查点蛋白Rad9。相比之下，Mrc1，一种识别复制应激所需的检查点蛋白，在对rereplication的反应中不起作用。引人注目的是，复制细胞会积累亚染色体DNA断裂产物。这些迅速而严重的后果表明，即使是有限和零星的狂犬病也可能对基因组造成重大损害。因此，即使是细胞周期中DNA复制调控的细微破坏，也可能使细胞易发生与肿瘤发生相关的基因组不稳定性。
To maintain genome stability, the entire genome of a eukaryotic cell must be replicated once and only once per cell cycle. in many organisms, multiple overlapping mechanisms block rereplication, but the consequences of deregulating these mechanisms are poorly understood. Here, we show that disrupting these controls in the budding yeast Saccharomyces cerevisiae rapidly blocks cell proliferation. Rereplicating cells activate the classical DNA damage-induced checkpoint response, which depends on the BRCA1 C-terminus checkpoint protein Rad9. In contrast, Mrc1, a checkpoint protein required for recognition of replication stress, does not play a role in the response to rereplication. Strikingly, rereplicating cells accumulate subchromosomal DNA breakage products. These rapid and severe consequences suggest that even limited and sporadic rereplication could threaten the genome with significant damage. Hence, even subtle disruptions in the cell cycle regulation of DNA replication may predispose cells to the genomic instability associated with tumorigenesis.