cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence.
cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence.
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cGAS 在有丝分裂过程中防止染色体端到端融合并促进复制衰老
DOI：
10.1007/s13238-021-00879-y
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发表时间：
2022-01
期刊：
影响因子：
21.1
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Li X;Li X;Xie C;Cai S;Li M;Jin H;Wu S;Cui J;Liu H;Zhao Y
作为胞浆DNA的感受器，环状GMP-AMP合成酶(CGAS)在先天免疫反应中的作用已被证实，但其在不同生物条件下的功能尚不清楚。在这里，我们发现cGAS在抑制有丝分裂DNA双链断裂(DSB)修复和保护短端粒不依赖于典型的cGAS-STING途径的端到端融合中是一个重要的调节因子。当TRF1/TRF2/POT1在端粒缺失时，cGAS在有丝分裂过程中与端粒/亚端粒DNA结合。CGAS的缺失导致有丝分裂染色体端到端的融合，主要发生在短端粒之间。从机制上讲，cGAS与CDK1相互作用，并将它们定位在染色体末端。因此，CDK1通过阻断RNF8的募集来抑制有丝分裂非同源末端连接(NHEJ)。CGAS基因缺陷的人类原代细胞在进入复制性衰老过程中存在缺陷，表现为染色体端到端融合、基因组不稳定和生长停滞时间延长。总之，cGAS通过控制有丝分裂DSB修复来抑制有丝分裂染色体的端到端融合，从而促进复制衰老，从而保护基因组的稳定性。
As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.
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影响因子：
21.3
作者：
Glück S;Guey B;Gulen MF;Wolter K;Kang TW;Schmacke NA;Bridgeman A;Rehwinkel J;Zender L;Ablasser A
通讯作者：
Ablasser A
DOI：
10.1038/s41577-021-00524-z
发表时间：
2021-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Decout A;Katz JD;Venkatraman S;Ablasser A
通讯作者：
Ablasser A
影响因子：
64.8
作者：
Dou Z;Ghosh K;Vizioli MG;Zhu J;Sen P;Wangensteen KJ;Simithy J;Lan Y;Lin Y;Zhou Z;Capell BC;Xu C;Xu M;Kieckhaefer JE;Jiang T;Shoshkes-Carmel M;Tanim KMAA;Barber GN;Seykora JT;Millar SE;Kaestner KH;Garcia BA;Adams PD;Berger SL
通讯作者：
Berger SL
影响因子：
16.8
作者：
Hayashi, Makoto T.;Cesare, Anthony J.;Karlseder, Jan
通讯作者：
Karlseder, Jan
影响因子：
64.5
作者：
Hemann, MT;Strong, MA;Greider, CW
通讯作者：
Greider, CW