1.5 DNA repair mechanism
DNA double strand breaks (DBSs) and single-strand breaks (SSBs) occur every day in cells and they are mostly caused by ionizing radiation, ultraviolet light, reactive oxygen species, errors during DNA replication, enzymes during meiosis. The repair of these DSBs and SSBs is essential to maintain genomic fidelity and stability. In order to combat DBSs and SSBs, cells have developed multiple distinct DNA repair mechanisms which detect damaged DNA, signal its presence and promote the repair of the damage (Jackson and Bartek, 2009). One of these mechanisms is base excision repair (BER). BER is a multi-step process that corrects non-bulky damage to bases resulting from oxidation, methylation, deamination, or spontaneous loss of the DNA base itself. In BER, DNA glycosylase recognises the damaged base and mediates base removal before proliferating cell nuclear antigen (PCNA), polymerase β and DNA ligase I or DNA Ligase III complete the repair process (Jackson and Bartek, 2009, David et al., 2007). Nucleotide excision repair (NER) is perhaps the most flexible of the DNA repair pathways. NER recognises and repairs lesions which are caused by helical distortion of the DNA duplex and pyrimidine dimers (cyclobutane pyrimidine dimers and 6-4 photoproducts) which are caused by the UV component of sunlight. Other NER substrates include bulky chemical adducts, DNA intrastrand crosslinks, and some forms of oxidative damage. Two distinct NER pathways exist: transcription-coupled NER which focuses on lesion blocking transcriptions and global genome NER which surveys the entire genome for distorting damage (Jackson and Bartek, 2009, David et al., 2007 ). DNA mismatch repair (MMR) pathway plays an essential role in the correc...
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...ing proteins. The large protein kinase, consisting of 4128 amino acids (aa), has a molecular weight of 469 kDA (33, 85-87). DNA-PKcs associates with the Ku70/80 heterodimer and forms a catalytic active DNA-PK holoenzyme (Falck et al., 2005). The kinase activity of DNA-PKcs is activated upon interaction with a free DNA. The protein can bind to DNA fragments in absence of the Ku complex. However its kinase activity appears to be much lower (Hammarsten and Chu, 1998). DNA-PKcs mediates the synapsis and ligation of the two DNA fragments (Block et al., 2004; Kysela et al., 2005). The auto-phosphorylation of DNA-PKcs results in the remodelling of DNA-Pk (Block et al., 2004). Moreover, DNA-PK phosphorylates the histons H2AX and H1.This might indicate that DNA-PK modifies chromatin structure to facilitate the access of other DNA repair complexes to DSBs (Kysela et al., 2005
The IC50 values of LJI308 against RSK1, 2, and 3 were about0.004 - 0.013 mmol/L. 10 μMLJI308 could bind to nearly 100% of theRSK2. LJI308 boundtheN-terminiofRSK1, RSK3, and RSK4 to a similar extent. LJI308 inhibited S6K1 with an IC50 of 0.8 mM. In both MDA-MB-231 and H358 cell lines, 1 μM and 10 μM LJI308 exihibited an inhibitory effect on colony formation and cell growthwith a different sensitivity[1]. In HTRY-LT cell lines,treating withLJI308 (1-10 µM) after4 or 8 days decreased the cellviability by up to 90%; while little to no effect wasobserved in the non-tumorigenic HTRZ cells [2].
... Thus, the loss of BRCA1 can result in defective DNA damage repair, abnormal centrosome duplication, cell-cycle arrest, growth retardation, increased apoptosis, genetic instability and tumorigenesis2. The study of BRCA1 mutation in mice may be used for new therapeutic approaches, although the cause of the mutation in BRCA gene is unclear.
Tomida J, Itaya A, Shigechi T, Unno J, Uchida E, Ikura M, Masuda Y, Matsuda S, Adachi J, Kobayashi M, Meetei AR, Maehara Y, Yamamoto K, Kamiya K, Matsuura A, Matsuda T, Ikura T, Ishiai M and Takata M. 2013. A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair. Nucleic Acids Res. 41: 6930-6941.
A permanent change in the DNA sequence which makes up a gene is what is referred to as gene mutation (Mahoney & Springer 2009). It is believed that gene mutation occurs in two ways: that is, it can be acquired in personal lifetime or inherited from a parent. Those that are passed from parents to the child are referred to as hereditary mutation. They acquire the name since they are present in the eggs and sperms or the germ cell. In this case, such kind of mutation is present all through one’s life in almost every cell in the body. A similarity in mutation and gene diversity is the change in the DNA sequence which makes both mutation and genetic diversity have related issues.
DNA methylation primarily occurs within sites in the DNA sequence known as CpG dinucleotides, which is a 2 base pair sequence involving a Cytosine bonded to a Guanine by a phosphodiester bond.
...l electrophoresis (SCGE) also known as comet assay has become one of the standard methods for assessing DNA damage, with applications ranging from testing genotoxicity, human bio-monitoring and molecular epidemiology to its use in fundamental research in DNA damage and repair (Collins, 2004). The comet assay is a simple method for detecting DNA strand breaks within cells in eukaryotes. The procedure of comet assay includes Embedding the cells in agarose in a microscope slide, followed by lysing of cells with detergent and high salts to form nucleotides containing supercoiled loops of DNA linked to the nuclear matrix, and then undergoing Electrophoresis at high pH, which results in formation of structures resembling as comets, observed by fluorescence microscopy. The intensity of the comet tail relative to the head reflects the number of DNA breaks (Collins, 2004).
In some organism PDK 2 activates AKT by phosphorylating it at S473 sequence in regulatory domain. Activated ATK further regulates many cellular downstream processes (Fig 2).
Apoptosis is a distinct form of a programmed cell death ( PCD) or cell suicide , first described by Kerr et. al. in the 1970s(1, 2). It is a normal physiological phenomenon that plays an important role in embryonic development, maintenance of tissue homeostasis and pathology(3) . Apoptosis triggered by exogenous and endogenous stimuli as radiation, oxidative stress and genotoxic chemicals. It is defined by characteristic changes in the nuclear morphology including chromatin condensation and fragmentation , overall cell shrinkage and formation of apoptotic cell bodies. Among the many markers of apoptosis, DNA fragmentation is...
... starts relaxing the supercoils and altering of DNA and interacts with DNA helicase SGS1 and plays a role in DNA recombination, also cellular aging and maintenance of genome stability. Alternate splicing results in multiple transcript variants. Additional spliced variants of the gene have been described, but their complete length is unknown.
Precise chromosomal DNA replication during S phase of the cell cycle is a crucial factor in the proper maintenance of the genome from generation to generation. The current “once-per-cell-cycle” model of eukaryotic chromosome duplication describes a highly coordinated process by which temporally regulated replicon clusters are sequentially activated and subsequently united to form two semi-conserved copies of the genome. Replicon clusters, or replication domains, are comprised of individual replication units that are synchronously activated at predetermined points during S phase. Bi-directional replication within each replicon is initiated at periodic AT-rich origins along each chromosome. Origins are not characterized by any specific nucleotide sequence, but rather the spatial arrangement of origin replication complexes (ORCs). Given the duration of the S phase and replication fork rate, adjacent origins must be appropriately spaced to ensure the complete replication of each replicon. Chromatin arrangement by the nuclear matrix may be the underpinning factor responsible for ORC positioning. The six subunit ORC binds to origins of replication in an ATP-dependent manner during late telophase and early G1. In yeast, each replication domain simply contains a single ORC binding site. However, more complex origins are characterized by an initiation zone where DNA synthesis may begin at numerous locations. A single round of DNA synthesis at each activated origin is achieved by “lic...
Yang, Q. (2009). Cellular senescence, telomere recombination and maintenance. Cytogenetic and Genome Research, 122(3-4), 211-8. Retrieved from http://search.proquest.com/docview/224206989?accountid=28496
Free radicals are highly reactive atoms or polyatomic ions that have unpaired valence electrons. These unpaired electrons can bind to organic compounds, changing the structure of the substance (Halliwell, B.). In most cases, oxygen-free radicals (OFRs) and reactive oxygen species (ROSs) are byproducts of metabolism. OFRs originate from the metabolic process in mitochondria when oxygen molecules accept an extra electron (Raha, S. et al). While oxygen is necessary for respiration, OFRs can bind to cellular components like DNA bases or the deoxyribose backbone of DNA, which plays a key-role in the aging process and is also linked to the development of certain cancers (Valko, M. et al). The ability of OFRs and ROSs to bind to DNA causes breaks in the structure of DNA and is the reason why these
EnodoV is encoded by nfi gene and the main function of this DNA protein is to repair DNA bases that have been damaged due to the exposure to the ultra-voilet radiation. These damaged DNA bases are known as deaminated
DNA manipulation is one of the sensational topic that exist in our contemporary society. Manipulating DNA basically means changing the forms or the structure DNA of certain thing to change the traits genetically. Some people believe that manipulating DNA have multiple risks. However, I firmly believe that there are relatively more benefits than dangers, and I am going to inform about those benefits. First, changing DNA could stop the problem of famine.
Discoveries in DNA, cell biology, evolution, and biotechnology have been among the major achievements in biology over the past 200 years with accelerated discoveries and insight’s over the last 50 years. Consider the progress we have made in these areas of human knowledge. Present at least three of the discoveries you find to be the most important and describe their significance to society, heath, and the culture of modern life.