Green Brian M, Li Joachim J
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143-2200, USA.
Mol Biol Cell. 2005 Jan;16(1):421-32. doi: 10.1091/mbc.e04-09-0833. Epub 2004 Nov 10.
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.
为维持基因组稳定性，真核细胞的整个基因组在每个细胞周期必须且只能复制一次。在许多生物体中，多种重叠机制可阻止重新复制，但对这些机制失调的后果却知之甚少。在此，我们表明，破坏芽殖酵母酿酒酵母中的这些控制会迅速阻断细胞增殖。重新复制的细胞会激活经典的DNA损伤诱导的检查点反应，该反应依赖于BRCA1 C端检查点蛋白Rad9。相比之下，Mrc1是识别复制应激所需的检查点蛋白，在对重新复制的反应中不起作用。引人注目的是，重新复制的细胞会积累亚染色体DNA断裂产物。这些快速而严重的后果表明，即使是有限且偶发的重新复制也可能对基因组造成重大损伤威胁。因此，即使DNA复制的细胞周期调控中存在细微干扰，也可能使细胞易患与肿瘤发生相关的基因组不稳定。
