RAD18 signals DNA polymerase IOTA to stalled replication forks in cells entering S-phase with DNA damage.
RAD18 signals DNA polymerase IOTA to stalled replication forks in cells entering S-phase with DNA damage.
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DOI：
10.1007/978-0-387-74911-2_16
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发表时间：
2008
影响因子：
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通讯作者：
Shelly Kakar;N. B. Watson;W. Mcgregor
中科院分区：
文献类型：
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作者：
Shelly Kakar;N. B. Watson;W. Mcgregor
内源性产生的活性氧和遗传毒性致癌物质可以共价修饰细胞DNA中的碱基。如果在细胞周期的S期之前未被识别和去除，则此类修饰可以阻断DNA复制叉进展。如果被阻断的分叉没有被解决，它们会导致双链断裂和细胞死亡。最近的数据表明，跨病变DNA合成（TLS）的过程是一个高度保守的机制，绕过病变的模板DNA。虽然尚未完全了解，但在酵母中，泛素连接酶（RAD 18）向易出错的Y家族聚合酶发出信号，以阻断叉，从而绕过具有潜在致突变后果的损伤。酵母蛋白的同源物在高等真核细胞中发现，包括人类。我们正在研究的假设是，RAD18作为一个近端信号的Y家族聚合酶绕过损伤，以类似于酵母的方式，但具有额外的复杂性层。在这里，我们报告说，RAD18积累在核灶紫外线照射后，只有在细胞进入S期与DNA损伤。这些病灶与增殖细胞核抗原（PCNA）共定位。此外，一种新发现的DNA聚合酶，poliota，也以损伤和S期依赖的方式形成核灶。这些数据支持我们的总体假设，即RAD18在阻断的分叉处积累并启动信号以招募TLS聚合酶。
Endogenously generated reactive oxygen species and genotoxic carcinogens can covalently modify bases in cellular DNA. If not recognized and removed prior to S-phase of the cell cycle, such modifications can block DNA replication fork progression. If blocked forks are not are not resolved, they result in double strand breaks and cell death. Recent data indicate that the process of translesion DNA synthesis (TLS) is a highly conserved mechanism for bypassing lesions in template DNA. Although not fully understood, in yeast a ubiquitin ligase (RAD18) signals error-prone Y family polymerases to the blocked fork to bypass the damage with potentially mutagenic consequences. Homologs of the yeast proteins are found in higher eukaryotic cells, including human. We are examining the hypothesis that RAD18 acts as a proximal signal to Y-family polymerases to bypass damage, in a manner analogous to yeast but with additional layers of complexity. Here we report that RAD18 accumulates in nuclear foci after UV irradiation only in cells entering S-phase with DNA damage. These foci co-localize with proliferating cell nuclear antigen (PCNA). In addition, a newly described DNA polymerase, pol iota, also forms nuclear foci in a damage-and S-phase dependent manner. These data support our overall hypothesis that RAD18 accumulates at blocked forks and initiates the signal to recruit TLS polymerases.