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Human Dna Repair Genes

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Last Updated: 02 July 2021

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General | Latest Info

The human genome, like other genomes, encodes information to protect its own integrity. Dna repair enzymes continuously monitor chromosomes to correct damaged nucleotide residues generated by exposure to carcinogens and cytotoxic compounds. Damage is partly the consequence of environmental agents such as ultraviolet light from the sun, inhaled cigarette smoke, or incompletely defined dietary factors. However, large proportion of DNA alterations are caused unavoidably by endogenous weak mutagens including water, reactive oxygen species, and metabolites that can act as alkylating agents. Very slow turnover of DNA consequently occurs even in cells that do not proliferate. Genome instability caused by a great variety of DNA - damaging agents would be an overwhelming problem for cells and organisms if it were not for DNA repair. On the basis of searches of current draft of human genome sequence, we compiled a comprehensive list of DNA repair genes. This inventory focuses on genes whose products have been functionally linked to recognition and repair of damaged DNA as well as those showing strong sequence homology to repair genes in other organisms. Readers desiring further information on specific genes should consult primary references and links available through accession numbers. Recent review articles on evolutionary relationships of DNA repair genes and common sequence motifs in DNA repair genes may also be helpful. Functions required for three distinct forms of excision repair are described separately. These are base excision repair, nucleotide excision repair, and mismatch repair. Additional sections discuss direct reversal of DNA damage, recombination and rejoining pathways for repair of DNA strand breaks, and DNA polymerases that can bypass DNA damage. Ber proteins excise and replace damaged DNA bases, mainly those arising from endogenous oxidative and hydrolytic decay of DNA. Dna glycosylases initiate this process by releasing a modified base. This is followed by cleavage of the sugar - phosphate chain, excision of abasic residue, and local DNA synthesis and ligation. Cell nuclei and mitochondria contain several related but nonidentical DNA glycosylases obtained through alternative splicing of transcripts. Three different nuclear DNA glycosylases counteract oxidative damage, and the fourth mainly excises alkylated purines. Remarkably, four of eight identified DNA glycosylases can remove uracil from DNA. Each of them has a specialized function, however. Ung, which is homologous to Escherichia coli UNG enzyme, is associated with DNA replication forks and corrects uracil misincorporated opposite adenine. Smug1, which is unique to higher eukaryotes, probably removes uracil that arises in DNA by deamination of cytosine. Mbd4 excises uracil and thymine specifically AT deaminate CpG and 5 - methyl - CpG sequences, and TDG removes ethenoC, product of lipid peroxidation, and also slowly removes uracil and thymine from AT GU and GT base pairs. The existence of multiple proteins with similar activities is a recurring theme in human DNA repair. Another illustration of this is a set of AT least four adenosine triphosphate - dependent DNA ligases encoded by three genes, with LIG3 - XRCC1 providing the main nick - joining function for BER.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Significance

Machinery to maintain genomic integrity has been divided into pathways that are responsible for repairing specific lesions that occur in DNA, although significant cross talk occurs between these pathways 7. These include pathways responsible for repairing double - strand breaks, for repairing base damage or adducts by base excision repair or bulky adducts by nuclear excision repair pathway, correction of base mismatches via mismatch repair, or direct repair of direct damage to bases by methyl - guanine methyl - transferase. Each of these pathways has been reviewed in depth elsewhere 7 8. Double - strand breaks are a potent tumorigenic type of DNA lesion. The main pathways involved in DSB repair are homologous recombination and non - homologous end joining and each pathway has alternative pathway, namely, single - strand annealing and alternative end joining respectively. Among these DSB repair pathways, HR is cells ' highest fidelity method of repairing double - strand DNA breaks as it uses intact homologous duplex sequence, usually sister chromatid, as template and is active only during S and G2 phases of the cell cycle. Specific lesions generated will influence methods for detecting defects in pathways and play an important role in micro - environmental phenotype of resulting malignancy. In addition to known DNA repair pathways, emerging evidence strongly suggests that APOBEC plays an important role in tumorigenesis 9. Apobec enzymes are involved in somatic hypermutation and virus protection, and are common cause of mutation in cancers 10. Apobec consists of a family of seven enzymatic DNA cytosine deaminases responsible for somatic hypermutation, class - switching recombination, and RNA viral defense. Although their precise roles are still unclear, they catalyze hydrolytic conversion of cytosine to uracil in single - strand DNA, which results in C > T transition. In turn, uracil is removed by BER and, when the site is abasic, synthesis adds cytosine opposite, resulting in C > G transversion. Thus, this combination of mutagenic repair accounts for APOBEC's mutational signature.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Results

Different DNA - Repair pathways exist and perform major roles AT both cellular and organismic levels. These pathways include the direct reversal pathway, mismatch Repair pathway, nucleotide excision Repair pathway, base excision Repair pathway, homologous recombination pathway, and Non - homologous end joining pathway. Mechanisms for these pathways will not be discussed in detail in this review; instead we will focus on functional consequences associated with their defects. In contrast to other DNA - damage repair pathways, direct reversal of DNA damage is not a multistep process and does not involve multiple proteins. Furthermore, unlike excision repair, direct reversal of DNA damage does not require excision of damage bases. An example of DNA lesion that is repaired by direct reversal is O 6 - alkylguanine. Alkylating agents can transfer methyl or ethyl groups to guanine, thereby modifying the base and interfering with its pairing with cytosine during DNA replication. Cytotoxic and mutagenic O 6 alkyl adduct in DNA is Repair by direct reversal, which is mediated by enzyme Ada in Escherichia coli and mammalian O 6 - methylguanine - DNA methyltransferase. Mgmt, also know as AGT, removes DNA adducts by transferring alkyl group from oxygen in DNA to cysteine residue in its active site. This reaction leads to reversal of base damage; however, alkylation of MGMT leads to its inactivation and subsequent ubiquitination and proteosomal degradation. Mgmt has attracted a great deal of attention, as certain anticancer chemotherapeutic drugs produce O 6 - alkylguanine, further supporting its role in modulating therapeutic response of tumors to these drugs. Mouse models for MGMT inactivation have been generate. These mutants were viable and showed no increase in spontaneous tumorigenesis. However, MGMT homozygous mice and cells were highly sensitive to chemotherapeutic alkylating agents such as methylnitrosourea. Mgmt homozygous mutant females, but not males, develop larger numbers of dimethylnitrosamine - inducing liver and lung tumors compared with controls. Additionally, transgenic mice over - expressing human MGMT or E. Coli Ada have also been generate. In response to alkylating carcinogens that produce O 6 - alkylguanine in DNA, these transgenic mice demonstrate significantly reduced susceptibility to developing cancers, including thymomas, liver tumors, and skin tumors. Alkb is another enzyme that mediates direct DNA damage reversal in E. Coli. This dioxygenase is involved in repair of alkylation damage, particularly 1 - methyladenine and 3 - methylcytosine. Two mammalian AlkB homologues, ABH2 and ABH3, have been shown to possess DNA - repair functions similar to bacterial AlkB. Similar to AlkB, ABH2 and ABH3 have the ability to repair 1meA and 3meC residues. However, whereas ABH2 prefers double - strand DNA, ABH3 and AlkB favour single - strand DNA and RNA. Further insight into the function of mammalian ABH2 and ABH3 come from studies of mice carrying targeted mutations of these genes. Mice deficient in ABH2, ABH3, or both, were viable. Abh2 /, but not ABH3 /, mice show age - dependent accumulation of 1meA in their genomic DNA. As in AlkB mutants in E.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Discussion

The first major step in phylogenomic analysis is determination of the presence and absence of homologs of genes of interest in different species. For analysis here, genes with established roles in DNA repair processes were identified by comprehensive review of literature. Likely homologs of these genes were identified by searching a variety of sequence databases using blast and blast2 search algorithms. The Conservative operational definition of homology was used to limit the number of false positive results. In some cases, this threshold was lower if other evidence suggests that homologs were highly divergent. Since this conservative approach might lead to false negatives, iterative search methods were used to increase the likelihood of identifying highly divergent homologs of reference protein. The presence and absence of homologs of genes in particular species was determined by searching for complete genome sequences. Homologs of Repair genes that had been clone from species for which complete genomes were not available were identified by searching against nr and EST databases AT National Center for Biotechnology. Amino - acid sequences of all putative homologs of a particular gene were align using clustalw program. Alignments were examined by eye to assess the reliability of homology assignments. In addition, block - motifs were made of alignments using blocks web server. These were then used for additional database searches to identify sequences containing motifs similar to those that were align together. The second major step in phylogenomic analysis is characterization of evolutionary relationships among all homologs of each gene. To do this, phylogenetic trees were generated for each group of homologs from sequence alignments by neighbor - joining and parsimony Methods of PAUP * program. Robustness of phylogenetic patterns was assessed using bootstrapping and by comparing phylogenetic trees generated with different algorithms. In the third major step in phylogenomic analysis, four main events in the history of each gene family are infer. The first step in identifying these events involves determining evolutionary distribution patterns for each gene. Edps, which are determined by overlaying gene presence / absence information onto evolutionary trees of species, reveal a great deal about the evolutionary history of particular genes. For example, if a gene is present in only one subsection of species tree, then it likely originated in that subsection. However, some EDPs do not have a single likely mechanism of generation and thus require further analysis before being used to identify specific evolutionary events. For example, uneven distribution pattern can be explained either by lateral transfer to species with unexpected presence of genes or by gene loss in species with unexpected absence. Ascertaining which event occurs can usually be accomplished by comparing gene tree to species tree and testing for congruence. If there has been lateral transfer in the past, then species trees and gene trees should be incongruent.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Materials and Methods

Sensitivity of lymphocytes to oxidative attack by H 2 O 2 in vitro, indicated by Strand breakage measure with comet assay. One hundred comets from each of two duplicate gels were analyse visually on a scale of 0 - 4, forming no detectable tail to almost all DNA in the tail. The overall score, between 0 and 400, is related to DNA break frequency. Individual values from 14 subjects. Data is presented in order 1 2 and 3 / day for all subjects. Actual orders vary and are indicated by style of line: long dashes; solid; short dashes. Mean comet assay scores before and after each kiwifruit supplementation phase. P values are given for each dose: boxed P value refers to pooled data. Effect of kiwifruit on expression of repair - related genes. Levels of APE1 and OGG1 mRNA were estimated in lymphocytes from three subjects taken before and after kiwifruit consumption. Amounts of cDNA generated with specific primers for 18S, APE1 and OGG1 in exponential phase of PCR were quantify, and the average yield is expressed here for APE1 and OGG1 relative to 18S.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Introduction

Dna Repair processes are of crucial importance for maintenance of genetic information of all organisms. The Stability of the genome is constantly endangered by environmental agents, endogenous metabolic process, eg reactive species inside cells, and errors of cellular processes involving DNA. Modifications of DNA can lead to mutations, which alter the coding sequence of DNA and can lead to cancer in humans and other mammals. Other DNA lesions interfere with normal cellular transactions, such as DNA replication or transcription, and are deleterious to cell. To counteract DNA damage, organisms have evolved various damage prevention and repair systems. These systems ensure stability of DNA and accurate transmission of genetic information by protecting the genome against a large number of different chemical and structural alterations. At the same time, random changes in DNA are viewed as the main source of genetic variability, and thus the driving force for evolution. In multicellular organisms, changes in DNA sequence and structure are responsible for eg differential production of antibodies by the immune system. Therefore, DNA Repair mechanisms have to balance noxious against beneficial effects of alterations in genome sequence and chemical structure. It has been proposed that DNA damage from endogenous sources gives rise to 20 000 lesions per mammalian cell per day, most of lesions being deaminations, spontaneous hydrolysis of N - glycosidic bond, alkylations, and damage by reactive oxygen or nitrogen species and lipid peroxidation products. Lesions are also caused by errors in the DNA metabolic process, including formation of single - and double - strand breaks, collapse of replication forks, and introduction of modified nucleic acid bases during DNA replication. Counting all together, daily 10 16 - 10 18 repair events occur in healthy adult men. Despite protection provided by these mechanisms, some of the damage escapes repair, and, in consequence, leads to mutations, ageing and various diseases, including carcinogenesis and neurodegeneration. Dna Repair is a very complicated process, involving many factors. For instance, to date, 168 genes that encode Proteins involved in DNA repair have been identified in the human genome. They are involved in diverse processes, starting from detection of damage site in DNA, through several steps of enzymatic transformation of damaged DNA, to recombination and signaling to stop cell cycle or initiate apoptosis. Another form of dealing with DNA damage is lesion bypass, which facilitates continuation of replication even when irremovable modifications occur, but does not guarantee proper recreation of the original sequence and frequently leads to mutation generated by Translesion synthesis polymerases. Numerous chemical and structural transformations leading from damaged DNA to repaired DNA can be described as pathways, comprising a series of reaction steps.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Background

Heterologous expression of human proteins in yeast has enabled researchers to discover new genes, acquire information about cellular DNA damage response pathways, and screen for effects of mutations in DNA Repair genes by functional assays. Discovery and characterization of new mammalian genes that encode proteins which operate in functionally conserved pathways in lower eukaryote has proven to be very insightful. Mutational analyses of human DNA repair genes by yeast genetic complementation studies have also helped to elucidate functional consequences of disease mutations as well as polymorphic variants that potentially affect DNA repair capacity and influence human health and aging. Moreover, novel functions of human DNA repair proteins have been discovered by genetic rescue experiments in yeast given its tractable nature. These concepts are discussed and examples provided to illustrate the power of yeast genetics to study functions of human proteins with important roles in DNA repair and maintenance of genomic stability. Ner, which is responsible for removal of bulky DNA lesions, represents one of the earliest DNA repair pathways to be studied by genetic complementation experiments using human genes expressed in corresponding yeast mutant backgrounds. Mutations in the XPD gene result in ultraviolet light - Sensitive skin cancer disorder Xeroderma Pigmentosum, and two other genetic diseases known as Cockayne Syndrome and trichothiodystrophy, which are distinct in their clinical and cellular appearance from one another and XP. Cs patients have some phenotypes that resemble accelerated aging and are characterized by neurological dysfunction, but not cancer. Ttd has diverse and highly variable clinical symptoms which include photosensitivity, icthyosis, sulfur - deficient brittle hair, physical and mental impairment. Clinical heterogeneity of XPD alleles is likely to reflect multifunctional roles of protein in DNA Repair as well as in RNA Polymerase II transcription because it is an integral component of basal transcription factor TFIIH. Expression of human XPD gene in S. Cerevisiae Rad3 mutant strain rescues lethality of yeast Rad3 deletion, suggesting that it could serve as a subunit in TFIIH complex to substitute for its yeast counterpart Rad3 to perform transcription. To assess the apparently complex involvement of XPD in transcription, genetic complementation studies of Rad3 mutant yeast strain with site - direct mutant alleles of XPD were perform. Replacement of invariant lysine in XPD Walker box with arginine abolishes ATPase and Helicase activity but does not affect ATP and DNA binding. This ATPase / Helicase defective XPD protein expressed in Rad3 mutant performs its vital role in transcription. Ttd patient mutation Arg 722 Trp, which encodes catalytically active XPD Helicase, failed to rescue viability of Rad3 mutant, suggesting that XPD - R722W protein encoded by mutant allele was defective in its protein interactions which prevent it from performing normally in transcription. In support of this notion, XPD - R722W protein was indeed found to be defective in its ability to bind p44 subunit of TFIIH.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Concluding Remarks

Dna damage causes cancer development when erroneous DNA repair leads to mutations of chromosomal aberration that activate oncogenes or inactivate tumor suppressors genes. When DNA damage persists and interferes with replication or transcription, DNA damage checkpoints trigger cellular senescence or apoptosis that inactivate or eliminate damaged cells and thus suppress tumorigenesis. Dna repair mechanisms prevent cancer by preventing mutations. Chemo - and radiotherapy often inflict DNA damage to halt cancer cell proliferation or trigger apoptotic demise of cancer cells. Dna damage occurs on a daily basis from endogenous and exogenous sources. Distinct DNA repair systems recognize and remove lesions. When damage remains unrepaired, DNA damage checkpoints can halt cell cycle or induce cellular senescence or apoptosis. Erroneous repair or replicative bypass of lesions can result in mutations and chromosomal aberrations. When mutations affect tumor suppressor genes or oncogenes, cells might transform into cancer cells. Therefore, DNA repair is essential for preventing tumor development. However, once cancer has develop, DNA damage can be exploited to reduce cancerous growth and evoke apoptotic demise of cancer cells. Thus, chemo - and radiotherapies are still today, over 60 years after having been first introduced into tumor therapy, important strategies to fight cancer. Give central role of genome instability in triggering and treating cancer, it is likely that genotoxic treatments will remain an important avenue of cancer therapy. Also, better understanding of DNA repair systems will allow therapies that specifically target select repair pathways. It will be of particular importance to gain a deeper understanding of how various DNA repair systems interact with each other in the context of cellular homeostasis and DNA metabolism in order to optimize targeted approaches to cancer therapy.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

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