PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1.
PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1.
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DOI：
10.1016/j.celrep.2016.06.030
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发表时间：
2016-07-19
期刊：
影响因子：
8.8
通讯作者：
Kubota T
中科院分区：
文献类型：
--
作者：
Johnson C;Gali VK;Takahashi TS;Kubota T
基因组维持因子Elg 1的缺失会导致严重的基因组不稳定性，从而导致癌症，但其潜在机制尚不清楚。Elg 1形成复制因子C样复合物Elg 1-RLC的主要亚基，其在复制期间从DNA中卸载环形聚合酶钳PCNA。在这里，我们表明，在elg 1 Δ酵母基因组不稳定性的主要原因是PCNA在DNA上的G2/M期的延长滞留。过度表达诱导的PCNA在DNA上的积累导致基因组不稳定。相反，易于分解的PCNA突变体缓解了PCNA积累，挽救了elg 1 Δ细胞的基因组不稳定性。保留的PCNA的共价修饰对elg 1 Δ基因组不稳定性的贡献很小。通过工程细胞周期调控ELG 1等位基因，我们表明，在S期DNA上PCNA的异常积累导致中度基因组不稳定性，其保留通过G2/M期加剧基因组不稳定性。我们的研究结果表明，PCNA卸载Elg 1-RLC是基因组维护的关键。PCNA在DNA上的积累导致基因组不稳定性解除PCNA在DNA上的积累拯救了elg 1 Δ细胞中的基因组不稳定性PCNA在DNA上滞留进入G2/M期导致缺乏Elg 1的细胞中的基因组不稳定性Elg 1-RLC的PCNA卸载对于基因组维持是至关重要的基因组维持因子Elg 1的缺失导致严重的基因组不稳定性。约翰逊等人发现Elg 1对PCNA的卸载对于基因组的维持是至关重要的，并且PCNA在DNA上保留到G2/M期导致缺乏Elg 1的细胞中基因组的不稳定性。
Loss of the genome maintenance factor Elg1 causes serious genome instability that leads to cancer, but the underlying mechanism is unknown. Elg1 forms the major subunit of a replication factor C-like complex, Elg1-RLC, which unloads the ring-shaped polymerase clamp PCNA from DNA during replication. Here, we show that prolonged retention of PCNA on DNA into G2/M phase is the major cause of genome instability in elg1Δ yeast. Overexpression-induced accumulation of PCNA on DNA causes genome instability. Conversely, disassembly-prone PCNA mutants that relieve PCNA accumulation rescue the genome instability of elg1Δ cells. Covalent modifications to the retained PCNA make only a minor contribution to elg1Δ genome instability. By engineering cell-cycle-regulated ELG1 alleles, we show that abnormal accumulation of PCNA on DNA during S phase causes moderate genome instability and its retention through G2/M phase exacerbates genome instability. Our results reveal that PCNA unloading by Elg1-RLC is critical for genome maintenance. PCNA accumulation on DNA causes genome instability Relieving PCNA accumulation on DNA rescues genome instability in elg1Δ cells PCNA retention on DNA into G2/M phase causes genome instability in cells lacking Elg1 PCNA unloading by Elg1-RLC is critical for genome maintenance Loss of the genome maintenance factor Elg1 causes serious genome instability. Johnson et al. find that PCNA unloading by Elg1 is critical for genome maintenance, and that PCNA retention on DNA into G2/M phase causes genome instability in cells lacking Elg1.