Before resuming, I'd like to emphasize that the attitude of not seeing pathology or aging as the result of permanent degradation from an ideal point, which is still the dominant view, but of seeing it as an imbalance between destruction and construction, an excess of either of which can have pathological consequences, opens up new avenues for the development of therapies. So this is not a purely gratuitous game we're playing.
While subtle modifications are taken care of by the BER system, the main steps of which (base removal, hydrolysis of the phosphodiester backbone, repair and DIA II.2 ligation) are described in detail last week, larger (bulkier) lesions of single-stranded DNA (often UV-induced) are capable of distorting the DNA helical structure. These lesions are dealt with via nucleotide excision repair (NER), rather than base excision repair as in the case of BER. This response involves several steps: (i) recognition of the lesion, (ii) a cut on either side of the lesion, (iii) filling in of the deleted part and (iv) ligation. This involves the coordinated activity of some thirty enzymes (DIA II.3). As well as repairing DNA globally (GG-NER for global genome) when lesions have a distorting effect on the come structure, for example a bond between two thymidines (DIA II.3), nucleotide excision repair (NER) also repairs modifications during transcription (RNA synthesis from DNA) (TC-NER for transcription-coupled NER), which can block the progress of RNA polymerase. These two systems differ in their lesion recognition mechanisms ((i) in DIA II.3), but use the same enzymes (ii to v in the same DIA II.3). We can see in the top right-hand corner that in one case it is the structural change due to the lesion that is recognized by RAD23B, and in the second case it is the arrest of RNA polymerase (Pol-II) that constitutes the signal. The rest is more or less the same in both cases, with helicases such as XBP and XDP unwinding the DNA, and TFIIH keeping the system open, giving access to the repair enzymes. The two XPF and XPG nuclease enzymes remove the entire damaged strand, and the DNA polymerase recopies the complementary strand before the ligase completes the job.
