Mechanism of the initial steps in transcription-coupled DNA repair (TCR)

酿酒酵母TCR的启动机制与哺乳动物细胞的TCR启动机制不同。虽然Cockayne综合征B组基因的缺失会严重抑制哺乳动物细胞中的TCR，但其酵母同系物Rad26的缺失只会轻微地损害TCR。遗传分析强烈表明酵母中有两种可供选择的TCR亚途径。第一个显性途径可能由Pol II与Rad26的相互作用启动，并依赖于一个非必需的Pol II亚基Rpb4。第二个TCR途径在缺乏Rpb4的情况下变得突出，并依赖于另一个非必需的Pol II亚基Rpb9。Rpb9介导的TCR途径的机制尚不清楚。由于缺乏可能致死的RPB4/RPB9双缺失突变体，通过遗传手段对其进行研究一直受到阻碍。对酵母中Rpb9依赖途径的分析可能会为TCR过程中与POL II相关的事件提供重要的见解。Rpb9亚基在Pol II周围的位置表明它可能在将NER因子招募到受损部位中发挥作用。Rpb9参与多种转录相关功能，如转录起始(起始点的选择)、转录延伸，最近还参与了Rpb1的泛素化和降解，以响应紫外线诱导的DNA损伤。该亚基还与大量参与转录延长和组蛋白修饰的因子(如TFIIS、TFIIE和SAGA)相互作用。这些因素中的哪一个在Rpb9介导的TCR途径中起着Rad26类似物的作用仍有待确定。

The mechanism of TCR initiation in S. cerevisiae is distinct from the TCR initiation in mammalian cells. While deletion of the Cockayne Syndrome Group B gene severely inhibits TCR in the mammalian cells, deletion of its yeast homologue Rad26 only slightly impairs the TCR. Genetic analyses strongly suggest two alternative TCR subpathways in yeast. The first, dominant pathway is probably initiated by Pol II interaction with Rad26, and is dependent on a non-essential Pol II subunit Rpb4. The second TCR pathway becomes prominent in the absence of Rpb4, and is dependent on another non-essential Pol II subunit Rpb9. The mechanism of the Rpb9-mediated TCR pathway is not well understood. Its investigation by genetic means has been hampered by the lack of the RPB4/RPB9 double deletion mutant, which is likely to be lethal. Analysis of the Rpb9-dependent pathway in yeast may provide important insights into the Pol II-related events during TCR. The location of the Rpb9 subunit on the perimeter of Pol II suggests its possible function in recruiting NER factors to the damaged site. Rpb9 is involved in multiple-transcription related functions such as transcription initiation (selection of the start site), transcription elongation, and recently in ubiquitination and degradation of rpb1 in response to UV-induced DNA damage. This subunit also interacts with a plethora of factors involved in transcription elongation and histone modification (like TFIIS, TFIIE, and SAGA). Which of these factors act as a Rad26 analogue in the Rpb9-mediated TCR pathway remains to be identified.