Damaging agents can cause the nucleotides making up DNA to mutate by chemical modification, but they can also cause the bonds between them to break. This separation is a chromosomal break in the DNA strand, which can occur across one strand, known as a single strand break (SSB), or both strands, known as a double strand break (DSB). The types of environmental factors that can induce chromosomal breaks include ionizing radiation (UV irradiation) and chemical carcinogens, such as those found in tobacco smoke and pollutants.
Some DNA repair processes induce double strand breaks as a step in the repair process, including nucleotide excision repair of pyrimidine dimers formed in response to UV damage. Thus, some chromosomal breaks are caused indirectly when a gene associated with the repair process is damaged by exposure to damaging agents, resulting in a mutation in the repair process.
Repairing Double Strand Breaks
Double strand breaks, nicks across both strands of a DNA sequence, result in blocked cell division and transcription. Because there is no template to indicate whether all nucleotides are present at the nicked ends, there is a potential of losing some sequence with DSBs. Due to the complexity, the DSB repair process is not without errors.
There are two repair mechanisms that re-establish the DNA structure after double strand breakage: homologous recombination and nonhomologous end-joining (NHEJ). These processes require proteins that are capable of locating the loose ends on both sides of the break, and the cellular machinery can then determine where ligation is needed.
Homologous Recombination
Homologous recombination is also known as crossover, a normal occurrence during meiosis that results in greater genetic diversity. The recombination process uses, depending on the stage at which the breakage occurs, the sister chromatid or the other copy of the chromosome in the cell as a template to repair the broken DNA strands. A portion of DNA is transferred from the template to the break on one strand and the ends ligated. The enzyme DNA polymerase can then use the repaired strand as a template to make the other broken strand. DNA polymerase also replaced the section removed from the template chromosome/chromatid.
Two of the genes involved in homologous recombination are BRCA1 and BRCA2, which are associated with breast cancer. Aberrant expression of the proteins involved in the repair process hinders completion of the process, leaving faulty DNA in the cell, a context that often leads to cancer.
Nonhomologous End Joining
The second repair process for chromosomal breaks is the direct ligation of the broken ends of the DNA. For the most part, this process does not have the benefit of complementary nucleotides to determine if a portion of sequence is missing from the DNA molecule. Mistakes in NHEJ can lead to translocation, and even repaired DSBs can lead to cancer.
Single Strand Breaks
Single strand breaks, a nick across one strand of a DNA sequence, are more easily repaired than DSBs. DNA polymerase can replace the missing nucleotides using the intact strand as the template. Repairing a double strand break
References:
Bradly and Taylor. Repair-induced DNA double strand breaks after ultra-violet light and either aphidocolin or 1-b-D-arabinofuranosylcytosine/hydroxyurea. Carcinogenesis, 1983.
Cotran, Kumar, Collins. Robbins’ Pathologic Basis of Disease. Sixth Edition.
Kato et al. Cytotoxicity of cigarette smoke condensate is not due to DNA double strand breaks: Comparative studies using radiosensitive mutant and wild-type CHO cells. International Journal of Radiation Biology, 2007.
Alicia Mae Prater - Alicia received her doctorate in Experimental Pathology in 2007. She has been a freelance writer and scientific editor since 2008.
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