BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domain
BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domain
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DOI：
10.1073/pnas.1120422109
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发表时间：
2012-05-01
影响因子：
11.1
通讯作者：
Singer, Dinah S.
中科院分区：
文献类型：
--
作者：
Devaiah, Ballachanda N.;Lewis, Brian A.;Singer, Dinah S.
溴结构域蛋白BRD 4最近已被鉴定为急性髓性白血病、多发性骨髓瘤、伯基特淋巴瘤、NUT中线癌、结肠癌和炎性疾病的治疗靶标;其丧失是转移性乳腺癌的预后标志。BRD 4还有助于调节细胞周期和癌基因、HIV和人乳头瘤病毒（HPV）的转录。尽管它在广泛的生物过程中发挥作用，但BRD 4功能的精确分子机制仍然未知。我们报告说，BRD 4是一种非典型的激酶，结合到RNA聚合酶II的羧基末端结构域（CTD），并直接磷酸化其丝氨酸2（Ser 2）位点在体外和体内的条件下，其他CTD激酶是无活性的。CTD Ser 2的磷酸化在体内被阻断其与染色质结合的BRD 4抑制剂抑制。我们发现BRD 4是一种RNA聚合酶II CTD Ser 2激酶，暗示它是真核转录的调节因子。
The bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic signature for metastatic breast cancer. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function remains unknown. We report that BRD4 is an atypical kinase that binds to the carboxyl-terminal domain (CTD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites both in vitro and in vivo under conditions where other CTD kinases are inactive. Phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin. Our finding that BRD4 is an RNA polymerase II CTD Ser2 kinase implicates it as a regulator of eukaryotic transcription.