PDF(Pubmed)
Abstract：
RNA polymerase II (RNAPII) transcription initiates bidirectionally at many human protein-coding genes. Sense transcription usually dominates and leads to messenger RNA production, whereas antisense transcription rapidly terminates. The basis for this directionality is not fully understood. Here, we show that sense transcriptional initiation is more efficient than in the antisense direction, which establishes initial promoter directionality. After transcription begins, the opposing functions of the endonucleolytic subunit of Integrator, INTS11, and cyclin-dependent kinase 9 (CDK9) maintain directionality. Specifically, INTS11 terminates antisense transcription, whereas sense transcription is protected from INTS11-dependent attenuation by CDK9 activity. Strikingly, INTS11 attenuates transcription in both directions upon CDK9 inhibition, and the engineered recruitment of CDK9 desensitises transcription to INTS11. Therefore, the preferential initiation of sense transcription and the opposing activities of CDK9 and INTS11 explain mammalian promoter directionality.
摘要：
RNA聚合酶II（RNAPII）转录在许多人类蛋白质编码基因中双向启动。有义转录通常占主导地位，并导致信使RNA的产生，而反义转录迅速终止。这种方向性的基础尚未完全理解。这里,我们表明有义转录启动比反义方向更有效，这建立了初始启动子方向性。转录开始后,整合子的核酸内切亚基的相反功能，INTS11和细胞周期蛋白依赖性激酶9(CDK9)维持方向性。具体来说,INTS11终止反义转录，而有义转录被CDK9活性保护免受INTS11依赖性衰减。引人注目的是，INTS11在CDK9抑制后减弱两个方向的转录，CDK9的工程化募集使转录脱敏至INTS11。因此,有义转录的优先启动以及CDK9和INTS11的相反活性解释了哺乳动物启动子的方向性。
