小柯机器人

丹麦癌症协会研究中心Francesco Cecconi及其研究小组发现，AMBRA1通过调节细胞周期蛋白D以确保S期开启和基因组完整性。这一研究成果于2021年4月14日在线发表在国际学术期刊《自然》上。

研究人员发现AMBRA1是细胞周期从G1期到S期过渡的上游主调节因子，从而防止了复制压力。使用细胞和分子方法与体内模型相结合，研究揭示了AMBRA1通过介导D型细胞周期蛋白降解来调节其丰度。

此外，通过控制从G1到S期的转变，AMBRA1有助于维持DNA复制过程中基因组的完整性，从而消除了发育异常和肿瘤生长。最后，研究人员确定CHK1激酶是AMBRA1缺陷型肿瘤的潜在治疗靶标。这些结果提高了人们对复制周期开启和基因组完整性调控的认知，并将AMBRA1-cyclin D途径确定为与胚胎发育和肿瘤发生过程中基因组稳定性紧密相关的重要细胞周期调节事件。

据悉，哺乳动物的发育、成年组织的动态平衡以及避免包括癌症在内的严重疾病需要精密调控细胞周期和保持基因组稳定。细胞基因组复制的关键细胞命运决定主要是由两个平行的信号传导途径调控，即MYC途径和细胞周期蛋白D-细胞周期蛋白依赖性激酶（CDK）-成视网膜细胞瘤蛋白（RB）途径。在癌症中，MYC和细胞周期蛋白D–CDK–RB通过通常发生错误调控，这导致基因组不稳定增加。自噬性肿瘤抑制蛋白AMBRA1与细胞增殖的调控有关，但其潜在的分子机制仍知之甚少。

附：英文原文

Title: AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity

Author: Emiliano Maiani, Giacomo Milletti, Francesca Nazio, Ss Grnbk Holdgaard, Jirina Bartkova, Salvatore Rizza, Valentina Cianfanelli, Mar Lorente, Daniele Simoneschi, Miriam Di Marco, Pasquale DAcunzo, Luca Di Leo, Rikke Rasmussen, Costanza Montagna, Marilena Raciti, Cristiano De Stefanis, Estibaliz Gabicagogeascoa, Gergely Rona, Nlida Salvador, Emanuela Pupo, Joanna Maria Merchut-Maya, Colin J. Daniel, Marianna Carinci, Valeriana Cesarini, Alfie Osullivan, Yeon-Tae Jeong, Matteo Bordi, Francesco Russo, Silvia Campello, Angela Gallo, Giuseppe Filomeni, Letizia Lanzetti, Rosalie C. Sears, Petra Hamerlik, Armando Bartolazzi, Robert E. Hynds, David R. Pearce, Charles Swanton, Michele Pagano, Guillermo Velasco, Elena Papaleo, Daniela De Zio, Apolinar Maya-Mendoza, Franco Locatelli, Jiri Bartek, Francesco Cecconi

Issue&Volume: 2021-04-14

Abstract: 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) pathway1,2. 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.

DOI: 10.1038/s41586-021-03422-5

Source: https://www.nature.com/articles/s41586-021-03422-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html