Pold3 is required for genomic stability and telomere integrity in embryonic stem cells and meiosis.
Pold3 is required for genomic stability and telomere integrity in embryonic stem cells and meiosis.
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Pold3 是胚胎干细胞和减数分裂中基因组稳定性和端粒完整性所必需的。
DOI：
10.1093/nar/gky098
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发表时间：
2018-04-20
影响因子：
14.9
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Zhou Z;Wang L;Ge F;Gong P;Wang H;Wang F;Chen L;Liu L
胚胎干细胞（ESCs）和减数分裂的特点是与DNA双链断裂（DSB）修复相关的同源重组相对较高。本研究表明，Pold3在小鼠ESCs和精母细胞的DSB修复、端粒维持和基因组稳定性中发挥重要作用。通过尝试使用CRISPR/Cas9或转录激活子样效应核酸酶产生Pold3缺陷小鼠，我们发现Pold3 （Pold3−/−）的完全缺失导致E6.5的早期胚胎致死。在Pold3-缺失（Pold3−/−）囊胚和Pold3诱导敲除（iKO） ESCs的生长过程中，都发生了快速的DNA损伤反应和大量细胞凋亡。虽然Pold3−/−ESCs无法实现，但Pold3 iKO导致DNA损伤反应增加，端粒丢失和染色体断裂，并伴有S期延长。同时，Pold3缺失导致繁殖应激、微核和非整倍体。此外，在Pold3+/−或Pold3敲低的ESCs中，DNA修复受损。此外，Pold3通过调控53BP1、RIF1、ATR和ATM通路介导DNA复制和修复。此外，随着年龄的增长，Pold3单倍不足（Pold3+/−）小鼠的精母细胞表现出DSB修复受损、端粒缩短和丢失以及染色体断裂，与Pold3 iKO ESCs类似。这些数据表明，Pold3通过抑制复制应激维持ESCs和减数分裂的端粒完整性和基因组稳定性。
Embryonic stem cells (ESCs) and meiosis are featured by relatively higher frequent homologous recombination associated with DNA double strand breaks (DSB) repair. Here, we show that Pold3 plays important roles in DSB repair, telomere maintenance and genomic stability of both ESCs and spermatocytes in mice. By attempting to generate Pold3 deficient mice using CRISPR/Cas9 or transcription activator-like effector nucleases, we show that complete loss of Pold3 (Pold3−/−) resulted in early embryonic lethality at E6.5. Rapid DNA damage response and massive apoptosis occurred in both outgrowths of Pold3-null (Pold3−/−) blastocysts and Pold3 inducible knockout (iKO) ESCs. While Pold3−/− ESCs were not achievable, Pold3 iKO led to increased DNA damage response, telomere loss and chromosome breaks accompanied by extended S phase. Meanwhile, loss of Pold3 resulted in replicative stress, micronucleation and aneuploidy. Also, DNA repair was impaired in Pold3+/− or Pold3 knockdown ESCs. Moreover, Pold3 mediates DNA replication and repair by regulating 53BP1, RIF1, ATR and ATM pathways. Furthermore, spermatocytes of Pold3 haploinsufficient (Pold3+/−) mice with increasing age displayed impaired DSB repair, telomere shortening and loss, and chromosome breaks, like Pold3 iKO ESCs. These data suggest that Pold3 maintains telomere integrity and genomic stability of both ESCs and meiosis by suppressing replicative stress.
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影响因子：
11.4
作者：
Herrera, E;Samper, E;Blasco, MA
通讯作者：
Blasco, MA
通过诱导端粒 DNA 损伤以及 ATRX 和 DAXX 功能障碍，将端粒酶切换为 ALT 机制
影响因子：
4.6
作者：
Hu Y;Shi G;Zhang L;Li F;Jiang Y;Jiang S;Ma W;Zhao Y;Songyang Z;Huang J
通讯作者：
Huang J
影响因子：
16.6
作者：
Ahuja AK;Jodkowska K;Teloni F;Bizard AH;Zellweger R;Herrador R;Ortega S;Hickson ID;Altmeyer M;Mendez J;Lopes M
通讯作者：
Lopes M
影响因子：
64.5
作者：
Hsu PD;Lander ES;Zhang F
通讯作者：
Zhang F
影响因子：
21.3
作者：
Chan, Kok Lung;Palmai-Pallag, Timea;Hickson, Ian D.
通讯作者：
Hickson, Ian D.