The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
Cell Rep. 2020 May 26;31(8):107675. doi: 10.1016/j.celrep.2020.107675.
Genome stability requires coordination of DNA replication origin activation and replication fork progression. RTEL1 is a regulator of homologous recombination (HR) implicated in meiotic cross-over control and DNA repair in C. elegans. Through a genome-wide synthetic lethal screen, we uncovered an essential genetic interaction between RTEL1 and DNA polymerase (Pol) epsilon. Loss of POLE4, an accessory subunit of Pol epsilon, has no overt phenotype in worms. In contrast, the combined loss of POLE-4 and RTEL-1 results in embryonic lethality, accumulation of HR intermediates, genome instability, and cessation of DNA replication. Similarly, loss of Rtel1 in Pole4 mouse cells inhibits cellular proliferation, which is associated with persistent HR intermediates and incomplete DNA replication. We propose that RTEL1 facilitates genome-wide fork progression through its ability to metabolize DNA secondary structures that form during DNA replication. Loss of this function becomes incompatible with cell survival under conditions of reduced origin activation, such as Pol epsilon hypomorphy.
基因组稳定性需要协调 DNA 复制原点的激活和复制叉的推进。RTEL1 是同源重组 (HR) 的调节剂，在秀丽隐杆线虫的减数分裂交叉控制和 DNA 修复中起作用。通过全基因组合成致死筛选，我们发现 RTEL1 和 DNA 聚合酶 (Pol) epsilon 之间存在必需的遗传相互作用。Pol epsilon 的辅助亚基 POLE4 的缺失在蠕虫中没有明显的表型。相比之下，POLE-4 和 RTEL-1 的缺失共同导致胚胎致死、HR 中间体的积累、基因组不稳定和 DNA 复制停止。同样，Pole4 小鼠细胞中 Rtel1 的缺失抑制细胞增殖，这与持续的 HR 中间体和不完全的 DNA 复制有关。我们提出 RTEL1 通过其代谢在 DNA 复制过程中形成的 DNA 二级结构的能力促进全基因组叉推进。在原点激活减少的情况下，例如 Pol epsilon 功能降低，这种功能的丧失与细胞存活变得不兼容。
