Genetics

What happens to Dna Double Strand Breaks



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Breaks in the DNA strand due to exposure to damaging agents can occur across one (single strand break, SSB) or both strands (double strand break, DSB). Types of environmental damage that can induce chromosomal damage of this type include ionizing radiation, such as UV irradiation, and chemical carcinogens, as those found in tobacco smoke. Some DNA repair processes also induce DSBs as a step in repairing the strand, including nucleotide excision repair after UVB -induced formation of pyrimidine dimmers. Similarly, some DSBs are caused indirectly by exposure to these agents; some agents damage a gene associated with the repair process, which then results in when the mutation is repaired DSBs.

What are DSBs?

Double strand breaks are nicks in the backbone of the DNA across both strands. This breaks results in blocked cell division and DNA transcription. Single strand breaks are more easily repaired by DNA polymerase replacing the missing nucleotides, using the intact strand as the template, but there is no template to indicate what replaces the breakage when both strands are cut. The cell requires proteins that are capable of locating the loose ends for both sides of the break that can then determine where a ligation is needed. Due to the complexity, the process is not without errors.

Repairing a double strand break

There are two repair mechanisms that reestablish the DNA structure after double strand breakage - homologous recombination and nonhomologous end-joining (NHEJ).

Homologous recombination uses the sister chromatid or the other copy of the chromosome in the cell (depending on the stage at which the breakage occurs) as a template to rejoin the DNA at its appropriate location. To put it simply, a portion of DNA is transferred to the break, ligating the ends of the strands. DNA polymerase can then use the strand as a template to make the other strand, on both the broken chromosome and the borrowed one. This process is also known as crossover and occurs frequently during meiosis, one method of increasing genetic diversity.

Two of the genes involved in homologous recombination are BRCA1 and BRCA2, genes associated with breast cancer. Basically, aberrant expression of the proteins involved in the repair process leaves faulty DNA that leads to cancer - a common etiology of the disease.

The second repair process is the direct ligation of the broken ends of the DNA, called nonhomologous end-joining. This process often does not benefit from complementary nucleotides to determine if sequence is missing. Mistakes in this process can lead to translocation, so even repaired DSBs can lead to cancer.

References:

Bradly and Taylor. Repair-induced DNA double strand breaks after ultra-violet light and either aphidocolin or 1-b-D-arabinofuranosylcytosine/hydroxyurea. Carcinogenesis. 4 (12), 1513-1517, 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. 83(9), 583-591, 2007.

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