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Concept
Homology directed repair
Summary
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.
HDR is important for suppressing the formation of cancer. HDR maintains genomic stability by repairing broken DNA strands; it is assumed to be error free because of the use of a template. When a double strand DNA lesion is repaired by NHEJ there is no validating DNA template present so it may result in a novel DNA strand formation with loss of information. A different nucleotide sequence in the DNA strand results in a different protein expressed in the cell. This protein error may cause processes in the cell to fail. For example, a receptor of the cell that can receive a signal to stop dividing may malfunction, so the cell ignores the signal and keeps dividing and can form a cancer. The importance of HDR can be seen from the fact that the mechanism is conserved throughout evolution. The HDR mechanism has also been found in more simple organisms, such as yeast.
The pathway of HDR has not been totally elucidated yet (March 2008). However, a number of experimental results point to the validity of certain models.
It is generally accepted that histone H2AX (noted as γH2AX) is phosphorylated within seconds after damage occurs. H2AX is phosphorylated throughout the area surrounding the damage, not only precisely at the break. Therefore, it has been suggested that γH2AX functions as an adhesive component for attracting proteins to the damaged location. Several research groups have suggested that the phosphorylation of H2AX is done by ATM and ATR in cooperation with MDC1.
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Non-homologous end joining
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair (HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber.
Homologous recombination
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 (usually DNA as in cellular organisms but may be also RNA in viruses). Homologous recombination is widely used by cells to accurately repair harmful DNA breaks that occur on both strands of DNA, known as double-strand breaks (DSB), in a process called homologous recombinational repair (HRR).
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