The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II
The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II
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DOI：
10.1128/mcb.25.12.5052-5060.2005
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发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Krek, W
中科院分区：
文献类型：
--
作者：
Yart, A;Gstaiger, M;Krek, W
HRPT 2肿瘤抑制基因的失活与遗传性甲状旁腺肥大-颌肿瘤综合征和散发性甲状旁腺肿瘤恶性肿瘤的发病机制有关HPRT 2基因产物parafibromin的细胞功能尚未确定。在这里，我们表明，parafibromin物理相互作用与人类直系同源的酵母Paf 1复合物的组成部分，包括PAF 1，LEO 1，和CTR 9，参与转录延伸和3'端加工。它还与RNA聚合酶II的大亚基的修饰形式相关，特别是在羧基末端结构域内丝氨酸5或2上磷酸化的那些，这对于转录周期中转录延伸和RNA加工机制的协调募集很重要。这些相互作用依赖于一个C-末端结构域的parafibromin，这是删除约。80%的临床相关突变。最后，RNAi诱导的下调parafibromin促进进入S期，这意味着parafibromin作为细胞周期进展的抑制剂的作用。总之，这些发现将肿瘤抑制因子parafibromin与转录延伸和RNA加工途径联系起来，作为PAF 1复合物和RNA聚合酶II结合蛋白。这一途径的功能障碍可能是大多数遗传性甲状旁腺癌病例的普遍现象。
Inactivation of the HRPT2 tumor suppressor gene is associated with the pathogenesis of the hereditary hyperparathyroidism-jaw tumor syndrome and malignancy in sporadic parathyroid tumors. The cellular function of the HPRT2 gene product, parafibromin, has not been defined yet. Here we show that parafibromin physically interacts with human orthologs of yeast Paf1 complex components, including PAF1, LEO1, and CTR9, that are involved in transcription elongation and 3' end processing. It also associates with modified forms of the large subunit of RNA polymerase II, in particular those phosphorylated on serine 5 or 2 within the carboxy-terminal domain, that are important for the coordinate recruitment of transcription elongation and RNA processing machineries during the transcription cycle. These interactions depend on a C-terminal domain of parafibromin, which is deleted in ca. 80 % of clinically relevant mutations. Finally, RNAi-induced downregulation of parafibromin promotes entry into S phase, implying a role for parafibromin as an inhibitor of cell cycle progression. Taken together, these findings link the tumor suppressor parafibromin to the transcription elongation and RNA processing pathway as a PAF1 complex- and RNA polymerase II-bound protein. Dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary parathyroid cancer.