These methods provide information as small as from the nanoscale to atomic level. Such methods involve X-ray crystallography, NMR, SAXS – small-angle X-ray scattering, DXMS – hydrogen-deuterium exchange mass spectrometry, etc. When different methods come together, the dynamics of DNA repair complexes can be studied in great details. This is very important because proteins are once again, related in the DNA replication process. Proteins structures are found to be connected to the coordination of steps within the DNA damage response and repair pathways. Because this process of repair generates toxic intermediates, strong “genetic selection” is required as the DNA is being restored. The repair is completed with a ligase resealing the DNA backbone. The pathway regenerates a 3’ terminal that will be extended using DNA polymerase with an undamaged strand as the template. The damage is first detected, removed, then eventually replaced with the correct DNA sequence. There are three steps in which DNA damage is involved. Thus, DNA repair and damage response are essential in the function of life. DNA is continually damaged by metabolites and toxicants. In this article, DNA damage responses are studied in aspects that reveal the role of protein in such pathways. “Structural Dynamics in DNA damage signaling and repair” was an article written by JJ Perry, Elizabeth Cotner-Gohara, Tom Ellenberger, and John A. This phosphorylation is the initial step in the signaling of DNA damage. The major regulators of cellular response to DNA damage are ATM and ATR kinases (ataxia telangiectasia mutated) through the regulation of phosphorylation of over 700 proteins. In mice lacking H2AX, immune system degradation and increased incidence of tumors are found. It is suggested that damaged induced phosphorylation of the histone variant H2AX indicates the sites of DNA breaks many other repair proteins also collect at these sites of H2AX accumulation. The repair protein RAD51 quickly collects into foci at sites of DNA damage. The most lethal form of DNA damage comes from ionizing radiation which causes breaks in the double stand. Cells come across DNA damage constantly, so the DDR pathway is vital to cell survival. If the damage is irreparable, the cell undergoes apoptosis, or programmed cell death, to avoid passing on the potentially lethal errors in DNA. This pathway serves to detect errors or abnormalities, propagate the detection signal, and activate systems to correct the issue. To combat these stresses and properly maintain the genome, the DDR pathway, or DNA damage response pathway has evolved. The human genome is under constant toxic stress from normal cellular conditions such as free radicals or errors in DNA replication, as well as extrinsic conditions such as UV radiation. 8.2 Nonhomologous DNA End Joining Pathway (NHEJ)ĭNA Injury Detection and Signaling.
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