Figure 12.

Three DNA lesion checkpoints for GG-NER and TC-NER. Check step 1: For GG-NER, XPC/HR23B detects base-pair disruption and helix distortion and binds to the DNA strand opposite to that carrying the lesion. This constitutes the initial lesion recognition. For TCR, CSB is recruited to a stalled Pol II to discriminate genuine DNA lesion-induced transcription arrest from other forms of transcriptional arrest, as diagrammed in panel a. At this step, CSB acts in conjunction with Pol II to mediate the initial recognition of DNA lesions that block transcription translocation. Check step 2: Core TFIIH is recruited to further verify the DNA lesion. In GG-NER, the XPD and XPB helicases in core TFIIH translocate the complex towards the lesion. This is the result of XPD tracking along the damage-containing strand in a 5´ to 3´ direction and XPB tracking along the opposite strand (non-damaged) in a 3´ to 5´ direction. In TCR, TFIIH is loaded downstream of the arrested Pol II-CSB complex, with XPD and XPB tracking the template and non-template strands, respectively. The XPD/XPB helicases in core TFIIH translocate towards the lesion, as is the case for GG-NER. As a result, Pol II-CSB is pushed upstream by TFIIH to expose the DNA lesion. Check step 3: XPA is recruited for a final validation of the TFIIH-recognized lesion and to ensure that only genuine NER lesions are subjected to dual incision by endonucleases ERCC1/XPF and XPG and downstream repair synthesis.