Life would not be possible without the ability to repair damaged DNA. Since replication errors, including mismatch, and harmful exogenous factors are everyday problems for a living organism, a broad repertoire of repair genes has evolved in prokaryotes and eukaryotes. The following types of DNA repair can be distinguished by their basic mechanisms: (1) excision repair to remove a damaged DNA site, such as a strand with a thymine dimer; (2) mismatch repair to correct errors of replication by excising a stretch of single-stranded DNA containing the wrong base; (3) repair of UV-damaged DNA during replication; and (4) transcription coupled repair in active genes.
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A. Excision repair
The damaged strand of DNA is distorted and can be recognized by a set of three proteins, the UvrA, UvrB, and UvrC endonucleases in prokaryotes and XPA, XPB, and XPC in human cells. This DNA strand is cleaved on both sides of the damage by an exonuclease protein complex, and a stretch of about 12 or 13 nucleotides in prokaryotes and 27 to 29 nucleotides in eukaryotes is removed. DNA repair synthesis restores the missing stretch and a DNA ligase closes the gap.
B. Mismatch repair
Mismatch repair corrects errors of replication. However, the newly synthesized DNA strand containing the wrong base must be distinguished from the parent strand, and the site of a mismatch identified. The former is based on a difference in methylation in prokaryotes. The daughter strand is undermethylated at this stage. E.coli has three mismatch repair systems: long patch, short patch, and very short patch. The long patch system can replace 1kb DNA and more. It requires three repair proteins, MutH, MutL, and MutS, which have the human homologues hMSH1, hMLH1, and hMSH2. Mutations in their respective genes lead to cancer due to defective mismatch repair. C. Replication repair of UV-damaged DNA DNA damage interferes with replication, especially in the leading strand. Large stretches remain unreplicated beyond the damaged site (in the 3? direction of the new strand) unless swiftly repaired. The lagging strand is not affected as much because Okazaki fragments (about 100 nucleotides in length) of newly synthesized DNA are also formed beyond the damaged site. This leads to an asymmetric replication fork and single-stranded regions of the leading strand. Aside from repair by recombination, the damaged site can be bypassed.
D. Double-strand repair by homologous recombination
Double-strand damage is a common consequence of γ radiation. An important human pathway for mediating repair requires three proteins, encoded by the genes ATM, BRCA1, and BRCA2. Their names are derived from important diseases that result from mutations in these genes: ataxia telangiectasia and hereditary predisposition to breast cancer (BRCA1 and BRCA2). ATM, a member of a protein kinase family, is activated in response to DNA damage (1). Its active form phosphorylates BRCA1at specific sites (2). Phosphorylated BRCA1 induces homologous recombination in cooperation with BRCA2 and mRAD5, the mammalian homologue of E. coli RecA repair protein (3). This is required for efficient DNA double-break repair. Phosphorylated BRCA1 may also be involved in transcription and transcription-coupled DNA repair (4). (Figure redrawn from Ventikaraman, 1999).