DNA repair

Journal of Cell Science, Feb 2004

Oliver Fleck, Olaf Nielsen

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DNA repair

0 Department of Genetics, Institute of Molecular Biology, University of Copenhagen , ster Farimagsgade 2A, DK-1353 Copenhagen K , Denmark Organisms are permanently exposed to endogenous and exogenous agents that damage DNA. If not repaired, such damage can result in mutations, diseases and cell death. The cellular responses to DNA damage include processes that deal with its consequences (e.g. tolerance and apoptosis) as well as direct correction of the damage by DNA repair mechanisms, which may require activation of checkpoint pathways. There are various forms of DNA damage, such as base modifications, strand breaks, crosslinks and mismatches. There are also numerous DNA repair pathways. Each repair pathway is directed to specific types of damage, and a given type of damage can be targeted by several pathways. Major DNA repair pathways are mismatch repair (MMR), nucleotide excision repair (NER), base excision repair (BER), homologous recombinational repair (HR), and non-homologous end joining (NHEJ). These MMSLHHG21MPSHM6S2 Stranddiscrimination Mediatedby PCNA? 3-5exonuclease? Exo1? Alkylation Oxidation Deamination Crosslinking Ionizing agents radiation G T<>T G T A A C MismatchesLoops dPiymriemrsidinBCeruolksyslaindkdsucts C APendo Pol Phosphodiesterase C Pol LigaseII XRCC1 C APendo PCNA RFC G C LigaseI C G Pol dRPase C G LigaseII XRCC1 - Exo1 Pol d , Pole PCNA RFC,RPA LigaseI Homologous recombinational repair (HR) pathways each require a number of proteins. By contrast, O-alkylated bases, such as O6-methylguanine can be repaired by the action of a single protein, O6-methylguanine-DNA methyltransferase (MGMT). MGMT removes the alkyl group in a suicide reaction by transfer to one of its cysteine residues. Photolyases are able to split covalent bonds of pyrimidine dimers produced by UV radiation. They bind to a UV lesion in a light-independent process, but require light (350-450 nm) as an energy source for repair. Another NER-independent pathway that can remove UV-induced damage, UVER, is present in only a few organisms, such as the yeast Schizosaccharomyces pombe. A key factor in UVER is the endonuclease Uve1/UVDE, which cuts 5 of various types of damage. Recent work has uncovered novel pathways, such as transcription-coupled BER, break-induced replication, and nucleotide incision repair as well as interconnections between known pathways. For simplicity, we do not consider these here. Although most repair proteins are usually homologous between organisms, their designations are often different. Here we generally use the names of human proteins. Mismatch repair The main task of MMR is to remove base mismatches and small insertion/ deletion loops (IDLs) introduced during replication. In Escherichia coli, the main players in MMR are MutS, MutL and MutH. MutH nicks the nonmethylated strand and thereby enables discrimination between the newly synthesized strand and the template. MMR is bidirectional, i.e. nicking and degradation can occur from either the 5 or 3 side of the mismatch. In eukaryotes, several MutS and MutL homologues are involved in MMR; MutH homologues appear to be absent. Inactivation of human MMR causes hereditary nonpolyposis colorectal cancer (HNPCC) and some types of sporadic tumor. In the course of human MMR, base mismatches are bound by the MutS-homologous heterodimer MSH2MSH6, while small IDLs can be bound by MSH2-MSH6 and MSH2-MSH3. Subsequently, the MutL-homologous heterodimer MLH1-PMS2 is recruited. Oliver Fleck and Olaf Nielsen AA AA XPB TFIH RPA XPD PCNA RFC,RPA LigaseI G =O C Non-homologous end joining (NHEJ) Pol Pold /e Base excision repair (BER) G APendo G Pol In some eukaryotes additional MutL homologues exist. These form heterodimers with MLH1 and may play a minor role in MMR. It is not yet understood how eukaryotes distinguish between the new and the old strand. Strand discrimination may be either mediated by the replication accessory factor PCNA or could be simply achieved by recognition of nicks, gaps or free 3 ends that are present in the nascent strand during replication. In a downstream step, the newly synthesized strand is degraded, which removes the mismatch. MMR patches are ~100 to >1000 nucleotides in length. EXO1 is involved in 5 to 3 excision. It is not yet clear which factors participate in 3 to 5 excision, but DNA Pol d and e and EXO1 may be involved. MMR is completed after DNA synthesis by the replication machinery and ligation of the remaining nick. Nucleotide excision repair NER removes a variety of forms of DNA damage, including photoproducts induced by UV and other bulky lesions. NER consists of two subpathways: global genome repair (GGR), which removes damage in the genome overall and transcription-coupled repair (TCR), which specifically repairs the transcribed strand of active genes. The main difference between GGR and TCR is the requirement for different factors during the initial recognition steps. UV-DDB, consisting of DDB1 and DDB2, and XP (...truncated)


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Oliver Fleck, Olaf Nielsen. DNA repair, Journal of Cell Science, 2004, pp. 515-517, 117/4, DOI: 10.1242/jcs.00952