Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2.
Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2.
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DOI：
10.1016/j.molcel.2016.09.010
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发表时间：
2016-11-03
期刊：
影响因子：
16
通讯作者：
Pagano, Michele
中科院分区：
文献类型：
--
作者：
Dankert, John F.;Rona, Gergely;Clijsters, Linda;Geter, Phillip;Skaar, Jeffrey R.;Bermudez-Hernandez, Keria;Sassani, Elizabeth;Fenyo, David;Ueberheide, Beatrix;Schneider, Robert;Pagano, Michele
SLBP（茎环结合蛋白）是H2 AFX和典型组蛋白mRNA加工、翻译和降解所必需的高度保守因子。我们确定了F-box蛋白细胞周期蛋白F，SCF（Skp 1-Cul 1-F-box蛋白）复合物的底物识别亚基，作为SLBP的G2泛素连接酶。SLBP通过非典型的CY基序与细胞周期蛋白F相互作用，并且该基序的突变阻止SLBP在G2中降解。SLBP稳定突变体的表达导致多聚核糖体上H2 AFX mRNA的加载增加，导致H2A.X（由H2 AFX编码）的表达增加。在G2的遗传毒性应激后，高水平的H2 A. X导致持续的γ H2 A. X信号传导、高水平的Tyr 142磷酸化的H2 A. X、高水平的p53和诱导细胞凋亡。我们建议，细胞周期蛋白F共同进化的脊椎动物H2 AFX mRNA的茎环的外观介导SLBP降解，从而限制H2A.X合成和细胞死亡后的遗传毒性应激。无脊椎动物没有细胞周期蛋白F，它们的H2 AFX同源物不含茎环。Dankert等人提出，细胞周期蛋白F与脊椎动物H2 AFX直向同源物中茎环的出现共同进化，以靶向SLBP在G2中降解，并防止S期以外的H2 AFX mRNA的SLBP依赖性调节。
SLBP (stem-loop binding protein) is a highly conserved factor necessary for the processing, translation, and degradation of H2AFX and canonical histone mRNAs. We identified the F-box protein cyclin F, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the G2 ubiquitin ligase for SLBP. SLBP interacts with cyclin F via an atypical CY motif, and mutation of this motif prevents SLBP degradation in G2. Expression of an SLBP stable mutant results in increased loading of H2AFX mRNA onto polyribosomes, resulting in increased expression of H2A.X (encoded by H2AFX). Upon genotoxic stress in G2, high levels of H2A.X lead to persistent γH2A.X signaling, high levels of H2A.X phosphorylated on Tyr142, high levels of p53, and induction of apoptosis. We propose that cyclin F co-evolved with the appearance of stem-loops in vertebrate H2AFX mRNA to mediate SLBP degradation, thereby limiting H2A.X synthesis and cell death upon genotoxic stress. Invertebrates do not have cyclin F and their H2AFX homologs do not contain stem-loops. Dankert et al. propose that cyclin F co-evolved with the appearance of stem-loops in vertebrate H2AFX orthologs to target SLBP for degradation in G2 and prevent SLBP-dependent regulation of H2AFX mRNA outside of S phase.
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影响因子：
16
作者：
Elia AE;Boardman AP;Wang DC;Huttlin EL;Everley RA;Dephoure N;Zhou C;Koren I;Gygi SP;Elledge SJ
通讯作者：
Elledge SJ
DOI：
10.1261/rna.053389.115
发表时间：
2015-11
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Brooks L 3rd;Lyons SM;Mahoney JM;Welch JD;Liu Z;Marzluff WF;Whitfield ML
通讯作者：
Whitfield ML
影响因子：
5.3
作者：
BONNER, WM;MANNIRONI, C;HATCH, CL
通讯作者：
HATCH, CL
影响因子：
64.8
作者：
Clarkson, MJ;Wells, JRE;Tremethick, DJ
通讯作者：
Tremethick, DJ
影响因子：
10.5
作者：
Kolev, NG;Steitz, JA
通讯作者：
Steitz, JA