Mammalian nucleotide excision repair (NER). NER removes a wide variety of helix-distorting lesions from DNA, including those induced by UV light . NER is executed by two different damage-detection mechanisms, which utilize the same machinery to excise and repair the damage. Transcription-coupled NER (TC-NER) is initiated by stalling of RNA polymerase 2 on a lesion present in the transcribed strand of active genes, and depends on recruitment of the CSA and CSB proteins. Other lesions are removed by global genome NER (GG-NER), which is initiated by the UV-DDB ubiquitin ligase complex and the heterotrimeric XPC/RAD23/CETN2 complex. Following detection, the transcription factor II H (TFIIH) complex is recruited, and unwinds a stretch of approximately 30 nucleotides around the damage, providing access for other repair factors. The DNA-binding proteins XPA and RPA are thought to stimulate the translocation and damage-verification activity of TFIIH and to stabilize and orient the XPF/ERCC1 and XPG endonucleases, which subsequently incise the DNA around the damage. After excision of the damaged strand, the resulting gap of 25 to 29 nucleotides is filled in by DNA synthesis and ligation, involving replication factors such as PCNA and RFC, DNA polymerases δ, ε and κ, and final sealing of the gap by DNA ligases I and III. For clarity, not all proteins known to be involved in NER are shown.