Biology subjects

Matkarimov, B. T.

Publications and source records attributed to Matkarimov, B. T..

4 recordsLinked to original sources

bioRxiv2024

Enhanced thermal stability enables human mismatch-specific thymine-DNA glycosylase to catalyse futile DNA repair

Human thymine-DNA glycosylase (TDG) excises T mispaired with G in a CpG context to initiate the base excision repair (BER) pathway. TDG is also involved in epigenetic regulation of gene expression by participating in active DNA demethylation. Here we demonstrate that under extended incubation time the full-length TDG (TDGFL), but not its truncated catalytic domain TDG (TDGcat) or methyl-binding protein 4 (MBD4) DNA glycosylase, exhibits a significant excision activity towards T and C in regular non-damaged DNA duplex in TpG/CpA and CpG/CpG contexts. Time course of the cleavage product generation under single-turnover conditions shows that the maximal rate of base excision (kobs) of TDGFL-catalysed excision of T in the T*A base pair (0.0014 - 0.0069 min-1) is 85 - 330-fold lower than that of T in T*G mismatch (0.47 - 0.61 min-1). Unexpectedly, TDGFL, but not TDGcat, exhibits prolonged enzyme stability under 37{degrees}C when incubated in the presence of equimolar concentration of non-specific DNA duplex, suggesting that the disordered N- and C-terminal domains of TDG can interact with DNA and stabilize the overall conformation of the protein. Noteworthy, TDGFL is able to excise 5-hydroxymethylcytosine (5hmC), but not 5-methylcytosine residues, from duplex DNA with the efficiency that could be physiologically relevant in post-mitotic cells. Our findings demonstrate that, under the experimental conditions used, TDG catalyses sequence context-dependent removal of T, C and 5hmC residues in regular DNA duplexes. We propose that in vivo this futile DNA repair may lead to formation of persistent single-strand breaks in non-methylated regions of chromosomal DNA.

biochemistry↗

bioRxiv2023

Chargaff's second parity rule lies at the origin of additive genetic interactions in quantitative traits to make natural selection possible.

Results and Discussion ABSTRACT Results and Discussion Methods Author contributions Competing interests Data availability References Continuous variation in complex traits enables natural selection Quantitative traits exhibit continuous normal distribution of phenotypic variations because of their polygenic, multi-locus nature. According to the infinitesimal model proposed by Fisher, continuous phenotypic variation of a quantitative trait, influenced by infinitely large number of genetic loci in a population, have normal distribution (Fig. 1a)29. Here we suggest that this bell-shaped distribution also reflects differential selective pressure or fitness of each individual in the population. For example, when cons ...

genomics↗

bioRxiv2020

XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature

Recent studies demonstrated a dramatically increased risk of leukemia in patients with a rare genetic disorder, Xeroderma Pigmentosum group C (XP-C), characterized by constitutive deficiency of global genome nucleotide excision repair (GG-NER). However, the genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyzed a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observed an average of 25-fold increase of mutation rates in XP-C vs. sporadic leukemia which we presume leads to its elevated incidence and early appearance. In all XP-C tumors predominant mutational process is characterized by a distinct mutational signature, highlighting a specific mutational pattern in the context of GG-NER deficiency. We observed a strong mutational asymmetry with respect to transcription and the direction of replication in XP-C tumors suggesting association of mutagenesis with bulky purine DNA lesions of probably endogenous origin. These findings suggest existence of a balance between formation and repair of bulky DNA lesions by GG-NER in human body cells which is disrupted in XP-C patients leading to internal cancers.

cancer biology↗

bioRxiv2019

DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance.

A variety of endogenous and exogenous factors induce chemical and structural alterations to cellular DNA, as well as errors occurring throughout DNA synthesis. These DNA damages are cytotoxic, miscoding, or both, and are believed to be at the origin of cancer and other age related diseases. A human cell, in addition to nuclear DNA, contains thousands copies of mitochondrial DNA (mtDNA), a double-stranded, circular molecule of 16,569 bp. It was proposed that mtDNA is a critical target for reactive oxygen species (ROS), by-products of the oxidative phosphorylation (OXPHOS), generated in the organelle during aerobic respiration. Indeed, oxidative damage to mtDNA are more extensive and persistent as compared to that of nuclear DNA. Although, transversions are the hallmarks of mutations induced by ROS, paradoxically, the majority of mtDNA mutations that occurred during ageing and cancer are transitions. Furthermore, these mutations exhibit a striking strand orientation bias: T[->]C/G[->]A transitions preferentially occur on the Light strand, whereas C[->]T/A[->]G on the Heavy strand of mtDNA. Here, we propose that the majority of mtDNA progenies, created after multiple rounds of DNA replication, are derived from the Heavy strand only, due to asymmetric replication of the DNA strand anchored to inner membrane via D-loop structure.

molecular biology↗