Intrastrand and Interstrand DNA Cross-links

UV radiation induces DNA damage in part by causing adjacent pyrimidines in the same strand to react with one another, forming intrastrand cross-links. The major DNA lesions produced are CPDs and 6-4 photoproducts [123]. Transcription bypass has been investigated at site-specific thymine-thymine (TT) CPDs, which are known to be the major DNA photoproducts formed in vivo, and at 6-4 photoproducts, which are also helix-distorting lesions. 

Studies using T7 RNA polymerase show that TT dimers block transcription, but to different extents depending on the specific isomer [51-53]. For example, TT CPDs in the cis-syn configuration pose less of a block to bypass than do the TT 6-4 photoproducts. Furthermore, either lesion only interferes with transcription elongation when it is present on the transcribed strand lesions on the nontranscribed 

Psoralen is among the agents that forms interstrand DNA cross-links. It is a photosensitizing agent found in plants and has been used in a therapeutic regimen along with UV-A to treat psoriasis and other skin disorders. Psoralen can intercalate into DNA, absorb UV-A, and subsequently react with DNA, principally at 

Psoralen interstrand cross-links pose strong blocks to T7 RNA polymerase, E. coli RNA polymerase, and RNA Pol II [54, 65, 81], which is to be expected since the double helix cannot unwind in the vicinity of the adduct. Psoralen monoadducts on the transcribed strand of DNA pose blocks to transcription as well. Historically, psoralen adducts are of great interest since they were among the first chemically induced lesions to be investigated for TC-NER. Interestingly, psoralen interstrand cross-links are subject to TC-NER, but the monoadducts are not [82]. 

Intrastrand and interstrand DNA cross-links are also formed in DNA by another important class of chemotherapeutic drugs-the cisplatins. The majority of the adducts formed in vivo and in vitro are 1,2-intrastrand d(GpG) and d(ApG) crosslinks that represent 80-90% of the bound platinum. In addition 1,3-intrastrand d(GpTpG) cross-links and a small percentage of interstrand cross-links and monofunctional adducts are formed [127]. 

---

Cisplatin Forms intrastrand and interstrand DNA cross-links binding to nuclear and cytoplasmic proteins Non-small cell and small cell lung cancer, breast cancer, bladder cancer, gastroesophageal cancer, head and neck cancer, ovarian cancer, germ cell cancer Nausea and vomiting Nephrotoxicity, peripheral sensory neuropathy, ototoxicity, nerve dysfunction... 

---