Translational control of a human CDKN1A mRNA splice variant regulates the fate of UVB-irradiated human keratinocytes.
Translational control of a human CDKN1A mRNA splice variant regulates the fate of UVB-irradiated human keratinocytes.
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DOI：
10.1091/mbc.e17-06-0362
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发表时间：
2018-01-01
影响因子：
3.3
通讯作者：
Wek RC
中科院分区：
文献类型：
--
作者：
Collier AE;Spandau DF;Wek RC
eIF 2的磷酸化和对UVB的综合应激反应通过一种机制具有细胞保护作用，该机制的特征是CDKN 1A的特定剪接变体的优先翻译，该剪接变体促进G1期阻滞和随后的DNA修复。响应于亚致死紫外线B（UVB）照射，人角质形成细胞瞬时阻断细胞周期的进展，以允许足够的时间进行DNA修复和细胞命运确定。这些细胞活动对于避免皮肤致癌作用的启动非常重要。这些过程的核心是通过GCN 2磷酸化eIF 2 α（eIF 2 α-P）抑制mRNA翻译的起始。与整体蛋白质合成减少的同时，eIF 2 α-P和伴随的整合应激反应（ISR）选择性地增强参与应激适应的mRNA的翻译。在这项研究中，我们阐明了eIF 2 α-P细胞保护作用的机制，在人角质形成细胞响应UVB。UVB诱导的eIF 2 α-P的缺失减少了G1期阻滞、DNA修复和细胞衰老，同时增强了人角质形成细胞的细胞死亡。全基因组翻译分析显示，eIF 2 α-P的这些关键适应性反应的机制涉及诱导编码p21（CIP 1/WAF 1）蛋白的CDKN 1A的表达。我们进一步表明，人CDKN 1A mRNA剪接变体4在应激诱导的eIF 2 α-P后优先翻译，其机制部分由位于CDKN 1A mRNA 5′-前导序列的上游ORF介导。我们得出结论，eIF 2 α-P是通过翻译CDKN 1A的特异性剪接变体，促进G1期阻滞和随后的DNA修复的机制来响应UVB的细胞保护作用。
Phosphorylation of eIF2 and the integrated stress response in response to UVB are cytoprotective by a mechanism featuring preferential translation of a specific splice variant of CDKN1A that facilitates G1 arrest and subsequent DNA repair. In response to sublethal ultraviolet B (UVB) irradiation, human keratinocytes transiently block progression of the cell cycle to allow ample time for DNA repair and cell fate determination. These cellular activities are important for avoiding the initiation of carcinogenesis in skin. Central to these processes is the repression of initiation of mRNA translation through GCN2 phosphorylation of eIF2α (eIF2α-P). Concurrent with reduced global protein synthesis, eIF2α-P and the accompanying integrated stress response (ISR) selectively enhance translation of mRNAs involved in stress adaptation. In this study, we elucidated a mechanism for eIF2α-P cytoprotection in response to UVB in human keratinocytes. Loss of eIF2α-P induced by UVB diminished G1 arrest, DNA repair, and cellular senescence coincident with enhanced cell death in human keratinocytes. Genome-wide analysis of translation revealed that the mechanism for these critical adaptive responses by eIF2α-P involved induced expression of CDKN1A encoding the p21 (CIP1/WAF1) protein. We further show that human CDKN1A mRNA splice variant 4 is preferentially translated following stress-induced eIF2α-P by a mechanism mediated in part by upstream ORFs situated in the 5′-leader of CDKN1A mRNA. We conclude that eIF2α-P is cytoprotective in response to UVB by a mechanism featuring translation of a specific splice variant of CDKN1A that facilitates G1 arrest and subsequent DNA repair.