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.

Related Research Articles

Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code. In nature mutagenesis can lead to cancer and various heritable diseases, but it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.

DNA repair Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.

Molecular lesion

A molecular lesion, or a point lesion, is damage to the structure of a biological molecule such as DNA, RNA, or protein. This damage may result in the reduction or absence of normal function, and in rare cases the gain of a new function. Lesions in DNA may consist of breaks or other changes in chemical structure of the helix, ultimately preventing transcription. Meanwhile, lesions in proteins consist of both broken bonds and improper folding of the amino acid chain. While many nucleic acid lesions are general across DNA and RNA, some are specific to one, such as thymine dimers being found exclusively in DNA. Several cellular repair mechanisms exist, ranging from global to specific, in order to prevent lasting damage resulting from lesions.

Nucleotide excision repair DNA repair mechanism

Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals, radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucleotide excision repair (NER), base excision repair (BER), and DNA mismatch repair (MMR). While the BER pathway can recognize specific non-bulky lesions in DNA, it can correct only damaged bases that are removed by specific glycosylases. Similarly, the MMR pathway only targets mismatched Watson-Crick base pairs.

Homologous recombination genetic recombination between identical or highly similar strands of genetic material

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids. It is widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks (DSB), in a process called homologous recombinational repair (HRR). Homologous recombination also produces new combinations of DNA sequences during meiosis, the process by which eukaryotes make gamete cells, like sperm and egg cells in animals. These new combinations of DNA represent genetic variation in offspring, which in turn enables populations to adapt during the course of evolution. Homologous recombination is also used in horizontal gene transfer to exchange genetic material between different strains and species of bacteria and viruses.

DNA polymerase II is a prokaryotic DNA-Dependent DNA polymerase encoded by the PolB gene.

Photolyases are DNA repair enzymes that repair damage caused by exposure to ultraviolet light. These enzymes require visible light both for their own activation and for the actual DNA repair. The DNA repair mechanism involving photolyases is called photoreactivation. They mainly convert pyrimidine dimers into a normal pair of pyrimidine bases.

Pyrimidine dimer

Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions. Ultraviolet light (UV) induces the formation of covalent linkages between consecutive bases along the nucleotide chain in the vicinity of their carbon–carbon double bonds. The dimerization reaction can also occur among pyrimidine bases in dsRNA —uracil or cytosine. Two common UV products are cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts. These premutagenic lesions alter the structure and possibly the base-pairing. Up to 50–100 such reactions per second might occur in a skin cell during exposure to sunlight, but are usually corrected within seconds by photolyase reactivation or nucleotide excision repair. Uncorrected lesions can inhibit polymerases, cause misreading during transcription or replication, or lead to arrest of replication. Pyrimidine dimers are the primary cause of melanomas in humans.

Richard D. Wood is an American molecular biologist specializing in research on DNA repair and mutation. He is known for pioneering studies on nucleotide excision repair (NER), particularly for reconstituting the minimum set of proteins involved in this process, identifying proliferating cell nuclear antigen (PCNA) as part of the NER complex and identifying mammalian repair polymerases.

Ataxia telangiectasia and Rad3 related Protein kinase that detects DNA damage and halts cell division

Serine/threonine-protein kinase ATR also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1) is an enzyme that, in humans, is encoded by the ATR gene. It is a large kinase of about 301.66 kDa. ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ATR is activated in response to single strand breaks, and works with ATM to ensure genome integrity.

DDB2

DNA damage-binding protein 2 is a protein that in humans is encoded by the DDB2 gene.

ERCC8 (gene)

DNA excision repair protein ERCC-8 is a protein that in humans is encoded by the ERCC8 gene.

DNA polymerase eta

DNA polymerase eta, is a protein that in humans is encoded by the POLH gene.

Homology directed repair

Homology directed repair (HDR) is a mechanism in cells to repair double-strand DNA lesions. The most common form of HDR is homologous recombination. The HDR mechanism can only be used by the cell when there is a homologous piece of DNA present in the nucleus, mostly in G2 and S phase of the cell cycle. Other examples of homology-directed repair include single-strand annealing and breakage-induced replication. When the homologous DNA is absent, another process called non-homologous end joining (NHEJ) takes place instead.

The term proofreading is used in genetics to refer to the error-correcting processes, first proposed by John Hopfield and Jacques Ninio, involved in DNA replication, immune system specificity, enzyme-substrate recognition among many other processes that require enhanced specificity. The proofreading mechanisms of Hopfield and Ninio are non-equilibrium active processes that consume ATP to enhance specificity of various biochemical reactions.

PARP inhibitor Pharmacological enzyme inhibitors of poly (ADP-ribose) polymerases

PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP).

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

DNA damage is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of base pairs. DNA damages cause changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly.

PrimPol

PrimPol is a protein encoded by the PRIMPOL gene in humans. PrimPol is a eukaryotic protein with both DNA polymerase and DNA Primase activities involved in translesion DNA synthesis. It is the first eukaryotic protein to be identified with priming activity using deoxyribonucleotides. It is also the first protein identified in the mitochondria to have translesion DNA synthesis activities.

Mutational signatures are characteristic combinations of mutation types arising from specific mutagenesis processes such as DNA replication infidelity, exogenous and endogenous genotoxin exposures, defective DNA repair pathways, and DNA enzymatic editing.

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. 1 2 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.
  9. ↑ 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.
  10. ↑ 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. ↑ 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. 1 2 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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