Postreplication_repair

Postreplication repair

Postreplication repair

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Postreplication repair is the repair of damage to the DNA that takes place after replication.

Some example genes in humans include:

Accurate and efficient DNA replication is crucial for the health and survival of all living organisms. Under optimal conditions, the replicative DNA polymerases ε, δ, and α can work in concert to ensure that the genome is replicated efficiently with high accuracy in every cell cycle. However, DNA is constantly challenged by exogenous and endogenous genotoxic threats, including solar ultraviolet (UV) radiation and reactive oxygen species (ROS) generated as a byproduct of cellular metabolism. Damaged DNA can act as a steric block to replicative polymerases, thereby leading to incomplete DNA replication or the formation of secondary DNA strand breaks at the sites of replication stalling. Incomplete DNA synthesis and DNA strand breaks are both potential sources of genomic instability. An arsenal of DNA repair mechanisms exists to repair various forms of damaged DNA and minimize genomic instability. Most DNA repair mechanisms require an intact DNA strand as template to fix the damaged strand.

DNA damage prevents the normal enzymatic synthesis of DNA by the replication fork.[1][2][3][4] At damaged sites in the genome, both prokaryotic and eukaryotic cells utilize a number of postreplication repair (PRR) mechanisms to complete DNA replication. Chemically modified bases can be bypassed by either error-prone[5] or error-free[6] translesion polymerases, or through genetic exchange with the sister chromatid.[7] The replication of DNA with a broken sugar-phosphate backbone is most likely facilitated by the homologous recombination proteins that confer resistance to ionizing radiation. The activity of PRR enzymes is regulated by the SOS response in bacteria and may be controlled by the postreplication checkpoint response in eukaryotes.[8][9]

The elucidation of PRR mechanisms is an active area of molecular biology research, and the terminology is currently in flux. For instance, PRR has recently been referred to as "DNA damage tolerance" to emphasize the instances in which postreplication DNA damage is repaired without removing the original chemical modification to the DNA.[10] While the term PRR has most frequently been used to describe the repair of single-stranded postreplication gaps opposite damaged bases, a more broad usage has been suggested.[8] In this case, the term PRR would encompasses all processes that facilitate the replication of damaged DNA, including those that repair replication-induced double-strand breaks.

Melanoma cells are commonly defective in postreplication repair of DNA damages that are in the form of cyclobutane pyrimidine dimers, a type of damage caused by ultraviolet radiation.[11][12] A particular repair process that appears to be defective in melanoma cells is homologous recombinational repair.[12] Defective postreplication repair of cyclobutane pyrimidine dimers can lead to mutations that are the primary driver of melanoma.

References

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    Rupp WD, Howard-Flanders P (January 1968). "Discontinuities in the DNA synthesized in an excision-defective strain of Escherichia coli following ultraviolet irradiation". Journal of Molecular Biology. 31 (2): 291–304. doi:10.1016/0022-2836(68)90445-2. PMID 4865486.
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    Lehmann AR (December 1972). "Post-replication repair of DNA in ultraviolet-irradiated mammalian cells. No gaps in DNA synthesized late after ultraviolet irradiation". European Journal of Biochemistry. 31 (3): 438–45. doi:10.1111/j.1432-1033.1972.tb02550.x. PMID 4675366.
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    di Caprio L, Cox BS (June 1981). "DNA synthesis in UV-irradiated yeast". Mutation Research. 82 (1): 69–85. doi:10.1016/0027-5107(81)90139-1. PMID 7022172.
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    Prakash L (1981). "Characterization of postreplication repair in Saccharomyces cerevisiae and effects of rad6, rad18, rev3 and rad52 mutations". Molecular & General Genetics. 184 (3): 471–8. doi:10.1007/bf00352525. PMID 7038396. S2CID 22330052.
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    Morrison A, Christensen RB, Alley J, Beck AK, Bernstine EG, Lemontt JF, Lawrence CW (October 1989). "REV3, a Saccharomyces cerevisiae gene whose function is required for induced mutagenesis, is predicted to encode a nonessential DNA polymerase". Journal of Bacteriology. 171 (10): 5659–67. doi:10.1128/jb.171.10.5659-5667.1989. PMC 210411. PMID 2676986.
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    Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, et al. (June 1999). "The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta". Nature. 399 (6737): 700–4. Bibcode:1999Natur.399..700M. doi:10.1038/21447. PMID 10385124. S2CID 4429698.
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    Zhang H, Lawrence CW (November 2005). "The error-free component of the RAD6/RAD18 DNA damage tolerance pathway of budding yeast employs sister-strand recombination". Proceedings of the National Academy of Sciences of the United States of America. 102 (44): 15954–9. Bibcode:2005PNAS..10215954Z. doi:10.1073/pnas.0504586102. PMC 1276054. PMID 16247017.
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    Callegari AJ, Kelly TJ (March 2007). "Shedding light on the DNA damage checkpoint". Cell Cycle. 6 (6): 660–6. doi:10.4161/cc.6.6.3984. PMID 17387276.
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    Lopes M, Foiani M, Sogo JM (January 2006). "Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions". Molecular Cell. 21 (1): 15–27. doi:10.1016/j.molcel.2005.11.015. PMID 16387650.
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    Friedberg EC (December 2005). "Suffering in silence: the tolerance of DNA damage". Nature Reviews. Molecular Cell Biology. 6 (12): 943–53. doi:10.1038/nrm1781. PMID 16341080. S2CID 22853897.
  11. [11]
    Brash DE, Seidman MM (January 2020). "Defective postreplication repair of UV photoproducts in melanoma: a mutator phenotype". Molecular Oncology. 14 (1): 5–7. doi:10.1002/1878-0261.12612. PMC 6944110. PMID 31821728.
  12. [12]
    Pavey S, Pinder A, Fernando W, D'Arcy N, Matigian N, Skalamera D, et al. (January 2020). "Multiple interaction nodes define the postreplication repair response to UV-induced DNA damage that is defective in melanomas and correlated with UV signature mutation load". Molecular Oncology. 14 (1): 22–41. doi:10.1002/1878-0261.12601. PMC 6944116. PMID 31733171.
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