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DNA methylation analysis using bisulfite sequencing data
Published in Altuna Akalin, Computational Genomics with R, 2020
DNA methylation is established by DNA methyltransferases DNMT3A and DNMT3B in combination with DNMT3L and maintained through cell division by the methyltransferase DNMT1 and associated proteins. DNMT3a and DNMT3b are in charge of the de novo methylation during early development. Loss of 5mC can be achieved passively by dilution during replication or exclusion of DNMT1 from the nucleus. Recent discoveries of the ten-eleven translocation (TET) family of proteins and their ability to convert 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) in vertebrates provide a path for catalyzed active DNA demethylation (Tahiliani et al., 2009). Iterative oxidations of 5hmC catalyzed by TET result in 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 5caC mark is excised from DNA by G/T mismatch-specific thymine-DNA glycosylase (TDG), which as a result reverts cytosine residue to its unmodified state (He et al., 2011). Apart from these, mainly bacteria, but possibly higher eukaryotes, contain base modifications on bases other than cytosine, such as methylated adenine or guanine (Clark et al., 2011).
MUTYH-Associated Polyposis
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Due to the fact that p.Y179C mutation significantly reduces MUTYH glycosylase activity in relation to pG396D mutation, patients with homozygous p.Y179C mutation often display more severe disease (including earlier presentation and higher colorectal cancer risk) than those with biallelic p.G396D or those with compound heterozygous p.G396D/p.Y179C [1].
Mitochondrial Genome Damage, Dysfunction and Repair
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Kalyan Mahapatra, Sayanti De, Sujit Roy
Mitochondrial BER pathway follows similar three-step mechanism like that of seen in nuclear BER pathway, i.e., recognition and elimination of damaged base, gap tailoring and DNA synthesis/ligation. Depending on the DNA polymerase mediated insertion of either single nucleotide or short sequence, BER pathway is of two types, i.e., short-patch BER and long-patch BER. Although animal mitochondria show both of them, plant mitochondria are restricted to short-patch BER only (Mecocci et al., 1993).The first step in Short patch BER is recognition of the damaged base and its elimination. The damaged base is recognized by two types of DNA glycosylase i.e., monofunctional and bifunctional.
Molecular radiobiology and the origins of the base excision repair pathway: an historical perspective
Published in International Journal of Radiation Biology, 2023
Ionizing radiation-damaged DNA was a good substrate for endonuclease III, endo VIII and formamidopyrimidine DNA glycosylase as well as a variety of endonucleases that recognize AP sites. Also, E. coli cells mutant in DNA polymerase I or DNA ligase (Paterson et al. 1971; Billen and Hellermann 1976; Zhang et al. 1992), were sensitive to the lethal effects of ionizing radiation. DNA glycosylases, AP endonucleases, repair DNA polymerases and DNA ligases turned out to be the four core enzymes in the Base Excision Repair Pathway (Figure 2), a pathway that evolved primarily to remove endogenous damages resulting from oxidative metabolism, alkylation and heat. However, because of the overlapping spectra of lesions produced by endogenous reactive oxygen species and radiation-induced reactive oxygen species, base excision repair is responsible for removing and repairing the vast majority of ionizing radiation-induced DNA damages.
A novel polymerase β inhibitor from phage displayed peptide library augments the anti-tumour effects of temozolomide on colorectal cancer
Published in Journal of Chemotherapy, 2022
Lihong Qin, Mao Huiwen, Jianguo Wang, Yuanyaun Wang, Salman A. Khan, Ying Zhang, Hong Qiu, Longwei Jiang, Lingfeng He, Yan Zhang, Shaochang Jia
Growing studies reveal that DNA repair pathways enable tumour cells to survive DNA damage induced by chemotherapeutic drugs [13]. BER is recognized as the predominant DNA repair pathway for eliminating small DNA base lesions in mammalian cells [14, 15]. Damaged base residues are removed by alkyladenine DNA glycosylase (Aag), a lesion-specific DNA glycosylase. Next the resulting abasic site is recognized by APE1 (an apurinic/apyrimidinic endonuclease) to incise the damaged strand, leaving 5 V deoxyribose phosphate (5’dRP) and 3’OH group at the margin. A DNA polymerase β (pol-β)–mediated DNA synthesis step fills the single nucleotide gap, and the 5’dRP lyase activity of pol-β, removes the cytotoxic 5’dRP group. Subsequent reactions are coordinated by PARP1 and/or XRCC1 with Pol β and DNA ligase completing the repair pathway. [16–18].
Consequences and repair of radiation-induced DNA damage: fifty years of fun questions and answers
Published in International Journal of Radiation Biology, 2022
Kayo Imamura, a post-doc in Sylvie’s lab determined the crystal structure of MvNei1 unliganded and bound to DNA containing an abasic site, THF (Imamura et al. 2009). The structure contains the same overall architecture as other members of the Fpg/Nei family. It also contains a ‘zincless finger’ as predicted by its sequence. Kayo also solved the MvNei1 structure bound to DNA containing Tg or 5-OHU, the first of any Nei glycosylase bound to a base lesion (Imamura et al. 2012). Both lesions were flipped out of the DNA in the glycosylase active site. There were only two protein side chains within hydrogen bonding contact with either damaged base and mutating these did not affect glycosylase activity. These data suggested that lesion recognition by Nei occurs before the base is flipped into the enzyme’s active site and was an important stimulus for our single molecule studies determining how glycosylases search for and locate the lesions they are to remove.