Figure 2: The two subpathways of mammalian NER. Physical or chemical agents like UV, cis-platin, or benzopyrene can damage DNA and induce damage-mediated helix distortions anywhere in the genome (GG-NER in green, bottom panel) or on the transcribed strand of a gene (TC-NER in red, top panel). Bottom panel: (I) XPC-RAD23B recognizes and binds to DNA damage-mediated helix distortion to initiate GG-NER. (II) TFIIH is recruited in an ATP-dependent manner, followed by XPA and RPA, which verify the presence of the lesion. During this step, the CAK module of TFIIH is released from the preincision complex [29]. (III) Within the preincision complex, ERCC1-XPF and XPG structure-specific endonucleases incise the damaged strand on the 5 and 3 sides of the lesion, respectively. Following incision, NER factors are released from the DNA, except XPG and RPA that favour the recruitment of the replication machinery composed of PCNA, RFC, and the DNA Polymerases 𝛿 , 𝜀 , or 𝜅 (ref). (IV) Following replication of the gap, the DNA is sealed by the ligase 1 (or the ligase III-XRCC1 complex in nondividing cells). Top Panel: (I) TC-NER is triggered by DNA damage-mediated blockage of RNA-Pol II (Top panel). (II) CSB is then recruited to the stalled RNA-Pol II enzyme and triggers the recruitment of the NER factors TFIIH, XPA, RPA, ERCC1-XPF, and XPG together with the CSA-CNS complex (III). (IV) Following the excision of the damaged oligonucleotide, the same DNA replication machinery of the GG-NER subpathway fills the gap created by the incision/excision step.