Nucleotide excision repair
From Wikipedia, the free encyclopedia
Nucleotide excision repair is a DNA repair mechanism. DNA constantly requires repair due to damage that can occur to bases from a vast variety of sources including chemicals but also ultraviolet (UV) light from the sun. Nucleotide excision repair (NER) is a particularly important mechanism by which the cell can prevent unwanted mutations by removing the vast majority of UV-induced DNA damage (mostly in the form of thymine dimers and 6-4-photoproducts). The importance of this repair mechanism is evidenced by the severe human diseases that result from in-born genetic mutations of NER proteins including Xeroderma pigmentosum and Cockayne's syndrome. While the base excision repair machinery can recognize specific lesions in the DNA and can correct only damaged bases that can be removed by a specific DNA glycosylase, the nucleotide excision repair enzymes recognize bulky distortions in the shape of the DNA double helix. Recognition of these distortions leads to the removal of a short single-stranded DNA segment that includes the lesion, creating a single-strand gap in the DNA, which is subsequently filled in by DNA polymerase, which uses the undamaged strand as a template. NER can be divided into two subpathways (Global genomic NER and Transcription coupled NER) that differ only in their recognition of helix-distorting DNA damage.
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[edit] Uvr Proteins
The process of nucleotide excision repair is controlled in E. coli by the UvrABC endonuclease enzyme complex, which consists of four Uvr proteins: UvrA, UvrB, UvrC, and DNA helicase II (sometimes also known as UvrD in this complex). First, a UvrA-UvrB complex scans the DNA, with the UvrA subunit recognizing distortions in the helix, caused for example by thymine dimers and other cyclobutyl dimers. When the complex recognizes such a distortion, UvrA exits and UvrB melts the base pairs between the two DNA strands. UvrB then recruits UvrC, which incises the DNA 8 nucleotides away from the distortion on the 5’ end and 4 nucleotides away on the 3’ end, creating a 12-nucleotide long single-stranded DNA that is excised with the help of the DNA helicase II. The resultant gap is then filled in using DNA polymerase I and DNA ligase. The basic excision process is very similar in higher cells, but these cells usually involve many more proteins – the E.coli example was merely used as a simple example.
[edit] Global genomic NER
Global genomic NER repairs damage in both transcribed and untranscribed DNA strands in active and inactive genes throughout the genome. This pathway employs several 'damage sensing' proteins including the DNA-damage binding (DDB) and XPC-Rad23B complexes that constantly scan the genome and recognize helix distortions. Upon identification of a damaged site, subsequent repair proteins are then recruited to the damaged DNA to verify presence of DNA damage, excise the damaged DNA surrounding the lesion then fill in the repair patch.
[edit] Transcription coupled repair
One of the interesting aspects of nucleotide excision repair is the transcription coupled repair mechanism. When RNA polymerase II is transcribing a gene and encounters a helix distorting thymine dimer, for example, it cannot continue transcription and stalls, recruiting nucleotide excision repair proteins to itself. This has two important consequences: (1) the RNA polymerase itself becomes a tool for recognizing DNA damage and (2) genes that are being actively transcribed are given more attention by the repair mechanisms. This is an especially important mechanism as persistently stalled RNA polymerase II results in either arrest of the cell cycle or pre-programmed cell death (apoptosis).
