Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis.
Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis.
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DOI：
10.1016/j.molcel.2018.04.008
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发表时间：
2018-05-17
期刊：
影响因子：
16
通讯作者：
Boulton SJ
中科院分区：
文献类型：
--
作者：
Bellelli R;Borel V;Logan C;Svendsen J;Cox DE;Nye E;Metcalfe K;O'Connell SM;Stamp G;Flynn HR;Snijders AP;Lassailly F;Jackson A;Boulton SJ
DNA聚合酶ε（POLE）是一种四亚基复合物，是真核生物中主要的前导链聚合酶。POLE 3和POLE 4的芽殖酵母直向同源物在体外促进Polε持续合成能力，但在体内的活力受到抑制。在这里，我们报告说，小鼠POLE 4缺乏使整个Polε复合物不稳定，导致近交系胚胎死亡，远交系广泛发育异常，白细胞减少和肿瘤易感性。在POLE 1中携带不稳定突变的人类患者中也观察到类似的生长迟缓和免疫缺陷表型。在Pole 4 −/−小鼠和POLE 1突变体人类细胞中，Polε亚型与复制应激和p53激活有关，我们将其归因于低效的复制起点激发。引人注目的是，去除p53足以挽救Pole 4缺失小鼠的胚胎致死率和所有发育异常。然而，Pole 4 −/−p53+/−小鼠表现出加速的肿瘤发生，揭示了控制CMG和起源激活在正常发育和肿瘤预防中的重要作用。Pole 4 −/−小鼠表现出发育受损和淋巴细胞成熟缺陷Pole 4对维持Polε复合体的稳定性至关重要Polε亚型通过低效的起始激活引起复制应激p53失活挽救了Pole 4缺陷小鼠的所有主要发育缺陷Bellelli et al.报道，小鼠中的Pole 4缺陷或人类中的POLE 1突变导致Pol Epidemic复合物不稳定、复制应激和低效的起始激活。因此，Pol Epidemiologic低形态小鼠表现出异常的生长和发育、淋巴细胞减少和肿瘤易感性，这可以通过删除p53来挽救。
DNA polymerase ε (POLE) is a four-subunit complex and the major leading strand polymerase in eukaryotes. Budding yeast orthologs of POLE3 and POLE4 promote Polε processivity in vitro but are dispensable for viability in vivo. Here, we report that POLE4 deficiency in mice destabilizes the entire Polε complex, leading to embryonic lethality in inbred strains and extensive developmental abnormalities, leukopenia, and tumor predisposition in outbred strains. Comparable phenotypes of growth retardation and immunodeficiency are also observed in human patients harboring destabilizing mutations in POLE1. In both Pole4−/− mouse and POLE1 mutant human cells, Polε hypomorphy is associated with replication stress and p53 activation, which we attribute to inefficient replication origin firing. Strikingly, removing p53 is sufficient to rescue embryonic lethality and all developmental abnormalities in Pole4 null mice. However, Pole4−/−p53+/− mice exhibit accelerated tumorigenesis, revealing an important role for controlled CMG and origin activation in normal development and tumor prevention. Pole4−/− mice exhibit impaired development and defective lymphocyte maturation Pole4 is crucial for maintaining the stability of the Polε complex Polε hypomorphy causes replication stress via inefficient origin activation p53 inactivation rescues all major developmental defects in Pole4-deficient mice Bellelli et al. report that Pole4 deficiency in mice or POLE1 mutations in humans result in Pol Epsilon complex instability, replication stress, and inefficient origin activation. As a consequence, Pol Epsilon hypomorphic mice exhibit aberrant growth and development, lymphopenia, and tumor predisposition, which can be rescued by deleting p53.
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