Deoxyribonucleic acid (DNA) is the genetic material of human cells. Changes in the DNA can disrupt cell function and result in disease, including cancer. Types of alterations include damage due to environmental effects and mistakes made during replication.
Strand Breaks
Environmental damage, including ionizing radiation and chemical alterations, can induce double strand breaks (DSBs). Double strand breaks are nicks in the backbone of the DNA across both strands, resulting in blocked cell division. Single strand breaks (SSBs), a nick of one strand, also occur. The SSBs are repaired by DNA polymerase replacing the missing nucleotides, using the intact strand as the template. There are two repair mechanisms that reestablish the DNA structure after double strand breakage – homologous recombination and nonhomologous end-joining.
Homologous recombination uses the sister chromatid or the other copy of the chromosome in the cell as a template to rejoin the DNA at its appropriate location. Nonhomologous end-joining is the direct joining of the broken ends with or without complementary nucleotides to determine exact placement. Proteins recognize the ends and bring them together for ligation. Mistakes in this process can lead to translocation, the relocation of portions of DNA to the wrong portion of the genome. Because of translocation, even repaired DSBs can lead to cancer.
Excision Repair
The presence of a damaged base, caused, for example, by oxidative damage, is removed and replaced in a process called base excision repair (BER). The enzymes DNA glycosylase, DNA polymerase beta, and DNA ligase are capable of removing, inserting, and patching the DNA strand, respectively. One of the most common point mutations is the addition of a methyl group to cytosine followed by deamination to thymine. Alkylation also occurs, frequently with chemotherapy. Some of these changes can be reversed as opposed to needing base excision.
Similarly, the insertion of the wrong nucleotide by the replication machinery, resulting in a failure to maintain normal Watson-Crick pairing, results in mismatched base pairs. Mismatch repair requires the recognition and removal of the wrongly inserted base, and then replacement with the appropriate base as well.
A slightly different process from BER is nucleotide excision repair (NER).The NER system removes a patch of nucleotides, not just the damage base. The patch is cut out of the unwound and opened DNA strand. The area is then filled in by the replication machinery in the same process as DNA synthesis. Nucleotide excision repair proceeds rapidly in cells actively undergoing transcription. An important gene in this process is XP (Xeroderma Pigmentosum), which is also the name of a rare genetic disorder caused by deviations in the repair process.
