AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity.
AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity.
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DOI：
10.1038/s41586-021-03422-5
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发表时间：
2021-04
期刊：
影响因子：
64.8
通讯作者：
Cecconi F
中科院分区：
文献类型：
--
作者：
Maiani E;Milletti G;Nazio F;Holdgaard SG;Bartkova J;Rizza S;Cianfanelli V;Lorente M;Simoneschi D;Di Marco M;D'Acunzo P;Di Leo L;Rasmussen R;Montagna C;Raciti M;De Stefanis C;Gabicagogeascoa E;Rona G;Salvador N;Pupo E;Merchut-Maya JM;Daniel CJ;Carinci M;Cesarini V;O'sullivan A;Jeong YT;Bordi M;Russo F;Campello S;Gallo A;Filomeni G;Lanzetti L;Sears RC;Hamerlik P;Bartolazzi A;Hynds RE;Pearce DR;Swanton C;Pagano M;Velasco G;Papaleo E;De Zio D;Maya-Mendoza A;Locatelli F;Bartek J;Cecconi F
哺乳动物的发育、成体组织的稳态和避免包括癌症在内的严重疾病需要适当协调的细胞周期以及无差错的基因组维持。复制基因组的关键细胞命运决定是由两个主要的信号传导途径控制的，这两个信号传导途径是并行作用的-MYC途径和细胞周期蛋白D-细胞周期蛋白依赖性激酶（CDK）-视网膜母细胞瘤蛋白（RB）途径。MYC和细胞周期蛋白D-CDK-RB轴通常在癌症中失调，这与基因组不稳定性增加有关。自噬肿瘤抑制蛋白AMBRA 1与细胞增殖的控制有关，但其潜在的分子机制仍知之甚少。在这里，我们表明，AMBRA 1是从G1期到S期的过渡的上游主调节器，从而防止复制应力。使用细胞和分子的方法和体内模型的组合，我们揭示了AMBRA 1调节D型细胞周期蛋白的丰度介导其降解。此外，通过控制从G1期到S期的过渡，AMBRA 1有助于在DNA复制期间保持基因组完整性，从而抵消发育异常和肿瘤生长。最后，我们确定CHK 1激酶作为AMBRA 1缺陷型肿瘤的潜在治疗靶点。这些结果推进了我们对复制阶段进入和基因组完整性控制的理解，并确定了AMBRA 1-细胞周期蛋白D途径作为一种重要的细胞周期调控机制，与胚胎发育和肿瘤发生中的基因组稳定性密切相关。
Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel—the MYC pathway and the cyclin D–cyclin-dependent kinase (CDK)–retinoblastoma protein (RB) pathway,. Both MYC and the cyclin D–CDK–RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1–cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis.
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
DOI：
10.1080/15384101.2017.1288322
发表时间：
2017-04-03
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Fragkos M;Naim V
通讯作者：
Naim V
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
影响因子：
10.5
作者：
Diehl, JA;Zindy, F;Sherr, CJ
通讯作者：
Sherr, CJ