AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair.
AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair.
复制标题
DOI：
10.1093/nar/gkw871
复制
发表时间：
2016-12-15
影响因子：
14.9
通讯作者：
D'Orazio JA
中科院分区：
文献类型：
--
作者：
Jarrett SG;Wolf Horrell EM;D'Orazio JA
黑素皮质素1受体(MC1R)是一种GS蛋白偶联受体，通过cAMP和蛋白激酶A(PKA)调节黑素细胞内的信号转导，是黑色素瘤的主要遗传危险因素。在这里，我们报道了一种新的cAMP介导的反应，以感知和响应紫外线诱导的DNA损伤，由A-激酶锚定蛋白12(AKAP12)调节。在S435，AKAP12被认为是PKA介导的共济失调毛细血管扩张突变和RAD3相关(ATR)磷酸化的必要参与者，这是cAMP增强的核苷酸切除修复(NER)所需的翻译后事件。此外，紫外线照射促进了AKAP12在S732的ATR导向的磷酸化，从而促进了AKAP12-ATR-pS435的核转位。这个复合体随后招募XPA来紫外线DNA损伤，并加强5‘链切割。阻止AKAP12的S与PKA或ATR的相互作用可阻止ATR-pS435的积累，延缓XPA对紫外线损伤的DNA的募集，损害NER并增加紫外线诱导的突变。我们的结果确定了AKAP12作为紫外光诱导的支架在PKA介导的ATR磷酸化中的关键作用，并在光损伤时发现了由AKAP12-ATR-pS435-xPA组成的修复复合体，这对cAMP增强的NER是必不可少的。
Loss-of-function in melanocortin 1 receptor (MC1R), a GS protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER). Moreover, UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, which promotes nuclear translocation of AKAP12–ATR-pS435. This complex subsequently recruits XPA to UV DNA damage and enhances 5′ strand incision. Preventing AKAP12's interaction with PKA or with ATR abrogates ATR-pS435 accumulation, delays recruitment of XPA to UV-damaged DNA, impairs NER and increases UV-induced mutagenesis. Our results define a critical role for AKAP12 as an UV-inducible scaffold for PKA-mediated ATR phosphorylation, and identify a repair complex consisting of AKAP12–ATR-pS435-XPA at photodamage, which is essential for cAMP-enhanced NER.
登录
查看更多内容
影响因子：
14.9
作者：
Kang TH;Reardon JT;Sancar A
通讯作者：
Sancar A
ATR在线粒体上扮演直接的抗凋亡作用，该抗凋亡作用受Prolyl异构酶PIN1的调节。
影响因子：
16
作者：
Hilton BA;Li Z;Musich PR;Wang H;Cartwright BM;Serrano M;Zhou XZ;Lu KP;Zou Y
通讯作者：
Zou Y
影响因子：
14.9
作者：
Bowles M;Lally J;Fadden AJ;Mouilleron S;Hammonds T;McDonald NQ
通讯作者：
McDonald NQ
影响因子：
4.3
作者：
Auclair, Yannick;Rouget, Raphael;Drobetsky, Elliot A.
通讯作者：
Drobetsky, Elliot A.
影响因子：
3.7
作者：
Ke R;Nong RY;Fredriksson S;Landegren U;Nilsson M
通讯作者：
Nilsson M