College of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 440-746, Republic of Korea.
Nucleic Acids Res. 2010 Jan;38(2):382-90. doi: 10.1093/nar/gkp991. Epub 2009 Nov 11.
Parafibromin, a component of the RNA polymerase II-associated PAF1 complex, is a tumor suppressor linked to hyperparathyroidism-jaw tumor syndrome and sporadic parathyroid carcinoma. Parafibromin induces cell cycle arrest by repressing cyclin D1 via an unknown mechanism. Here, we show that parafibromin interacts with the histone methyltransferase, SUV39H1, and functions as a transcriptional repressor. The central region (128-227 amino acids) of parafibromin is important for both the interaction with SUV39H1 and transcriptional repression. Parafibromin associated with the promoter and coding regions of cyclin D1 and was required for the recruitment of SUV39H1 and the induction of H3 K9 methylation but not H3 K4 methylation. RNA interference analysis showed that SUV39H1 was critical for cyclin D1 repression. These data suggest that parafibromin plays an unexpected role as a repressor in addition to its widely known activity associated with transcriptional activation. Parafibromin as a part of the PAF1 complex might downregulate cyclin D1 expression by integrating repressive H3 K9 methylation during transcription.
成纤维母细胞瘤抑制蛋白（Parafibromin）是 RNA 聚合酶 II 相关 PAF1 复合物的一个组成部分，它是与甲状旁腺功能亢进-颌骨肿瘤综合征和散发性甲状旁腺癌相关的肿瘤抑制因子。成纤维母细胞瘤抑制蛋白通过未知机制抑制细胞周期蛋白 D1 的表达从而诱导细胞周期停滞。在这里，我们发现成纤维母细胞瘤抑制蛋白与组蛋白甲基转移酶 SUV39H1 相互作用，并作为转录抑制因子发挥作用。成纤维母细胞瘤抑制蛋白的中心区域（128-227 个氨基酸）对于与 SUV39H1 的相互作用和转录抑制都是必需的。成纤维母细胞瘤抑制蛋白与细胞周期蛋白 D1 的启动子和编码区结合，并且需要招募 SUV39H1 并诱导 H3 K9 甲基化，但不需要诱导 H3 K4 甲基化。RNA 干扰分析表明 SUV39H1 对于细胞周期蛋白 D1 的抑制是至关重要的。这些数据表明，除了其广泛的与转录激活相关的活性外，成纤维母细胞瘤抑制蛋白还出人意料地发挥了转录抑制子的作用。作为 PAF1 复合物的一部分，成纤维母细胞瘤抑制蛋白可能通过在转录过程中整合抑制性的 H3 K9 甲基化来下调细胞周期蛋白 D1 的表达。
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