Repair of Thymine Dimers in E. coli
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Repair of Thymine Dimers in E. coli
UV radiation induces two of the most abundant mutagenic and cytotoxic DNA lesions such as CPD  (Cyclobutane-Pyrimidine Dimers) or 6-4PPs (6-4 Pyrimidine Pyrimidone). The most common covalently linked adjoining pyrimidines are TT(Thymine dimers), T-C (Thymine-Cytosine dimers) and C-C (Cytosine-Cytosine dimers). T-T dimers cause kinks in the DNA strand that prevent both replication and transcription of that part of the DNA. Because they block DNA replication (and therefore prevent cells from reproducing), T-T dimers and other forms of UV damage cannot be inherited, and thus do not constitute mutations. Such kinds of DNA damage are known as premutational lesions because they prevent both transcription and replication of the genes in which they are present and these lesions are fatal if they go uncorrected (Ref.2).

Several mechanisms are available for the removal or correction of pyrimidine dimers from DNA depending upon the circumstances of the cell. These include photoreactivation, mutagenic repair or dimmer bypass, recombinational repair, cell-cycle checkpoints and apoptosis, which are operative in various organisms for the removal or correction of T-T dimers (Ref.2). Pyrimidine dimers may also be mended by a process known as NER  (Nucleotide Excision Repair). In such repair pathways, an oligonucleotide containing the lesion is excised from the DNA and the resulting single-strand gap is filled in. In E.coli, a multisubunit enzyme, the product of the UVRA, UVRB and UVRC genes, recognizes pyrimidine dimers. Two molecules of UVRA and one of UVRB form a complex that moves randomly along DNA. Once the complex encounters a lesion, conformational changes in DNA, powered by ATP hydrolysis, cause the helix to become locally denatured and kinked by 130°. After the UVRA dimmer dissociates, the UVRC Endonuclease binds and cuts the damaged strand at two sites separated by 12 or 13 bases. UVRB and UVRC then dissociate, and Helicase-II unwinds the damaged region, releasing the single-stranded fragment with the lesion, which is degraded to mononucleotides. The gap is then filled by Pol-I (DNA Polymerase-I), and the remaining nick is sealed by DNA Ligase (Ref.1).

UVRABC Endonuclease excises other types of DNA lesions besides pyrimidine dimers. These lesions are characterized by the displacement of bases from their normal positions, as with pyrimidine dimers, or by the addition of a bulky substituent to a base. In E. coli NER, the UVRB-DNA preincision complex plays a key role, linking adduct recognition to incision (Ref.3).