mTOR regulates DNA damage response through NF-κB-mediated FANCD2 pathway in hematopoietic cells.
mTOR regulates DNA damage response through NF-κB-mediated FANCD2 pathway in hematopoietic cells.
复制标题
作者：
造血干/祖细胞（HSPC）的功能是产生成熟的血细胞。有效的DNA损伤反应（DDR）和基因组稳定性的维持对于HSPC的正常功能至关重要。哺乳动物雷帕霉素靶蛋白（mTOR）整合来自营养素和生长因子的信号以控制蛋白质合成、细胞生长、存活和代谢，并且已显示通过p53/p21信号级联调节酵母和人类癌细胞中的DDR。在这里，我们表明HSPC中mTOR的基因靶向由于各种DNA损伤剂而导致有缺陷的DDR，模拟由FANCD 2缺陷引起的DDR，FANCD 2是范可尼贫血（FA）DDR机制的关键组成部分。从机制上讲，mTOR −/− HSPC表达的FANCD 2急剧减少。与这些遗传发现一致，通过pp 242或Torin 1（mTOR激酶抑制剂）使人淋巴母细胞中的mTOR失活，抑制FANCD 2表达并导致缺陷性DDR，其可以通过外源性FANCD 2的重建来挽救。进一步的机制研究表明mTOR缺陷或失活增加了核因子（NF）-κB的磷酸化和核转位，这导致NF-κ B与FANCD 2启动子的结合增强，从而抑制FANCD 2表达。因此，mTOR通过涉及NF-κ B介导的FANCD 2表达的非经典途径调节造血细胞中的DDR和基因组稳定性。
Hematopoietic stem/progenitor cells (HSPCs) function to give rise to mature blood cells. Effective DNA damage response (DDR) and maintenance of genomic stability are crucial for normal functioning of HSPCs. Mammalian target of rapamycin (mTOR) integrates signals from nutrients and growth factors to control protein synthesis, cell growth, survival and metabolism, and has been shown to regulate DDR in yeast and human cancer cells through the p53/p21 signaling cascade. Here, we show that gene targeting of mTOR in HSPCs causes a defective DDR due to a variety of DNA damage agents, mimicking that caused by deficient FANCD2, a key component of the Fanconi anemia (FA) DDR machinery. Mechanistically, mTOR −/− HSPCs express drastically reduced FANCD2. Consistent with these genetic findings, inactivation of mTOR in human lymphoblast cells by pp242 or Torin 1, mTOR kinase inhibitors, suppresses FANCD2 expression and causes a defective DDR that can be rescued by reconstitution of exogenous FANCD2. Further mechanistic studies show that mTOR deficiency or inactivation increases phosphorylation and nuclear translocation of nuclear factor (NF)-κB, which results in an enhanced NF-kB binding to FANCD2 promoter to suppress FANCD2 expression. Thus, mTOR regulates DDR and genomic stability in hematopoietic cells through a noncanonical pathway involving NF-κB-mediated FANCD2 expression.
登录
查看更多内容
影响因子：
11.2
作者：
Yarde, Danielle N.;Oliveira, Vasco;Dalton, William S.
通讯作者：
Dalton, William S.
影响因子：
23.9
作者：
Ceccaldi, Raphael;Parmar, Kalindi;Mouly, Enguerran;Delord, Marc;Kim, Jung Min;Regairaz, Marie;Pla, Marika;Vasquez, Nadia;Zhang, Qing-Shuo;Pondarre, Corinne;de Latour, Regis Peffault;Gluckman, Eliane;Cavazzana-Calvo, Marina;Leblanc, Thierry;Larghero, Jerome;Grompe, Markus;Socie, Gerard;D'Andrea, Alan D.;Soulier, Jean
通讯作者：
Soulier, Jean
影响因子：
64.8
作者：
Rossi, Derrick J.;Bryder, David;Weissman, Irving L.
通讯作者：
Weissman, Irving L.
影响因子：
15.9
作者：
Kee, Younghoon;D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
影响因子：
64.5
作者：
Celeste, A;Difilippantonio, S;Nussenzweig, A
通讯作者：
Nussenzweig, A