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Acta Bio-medica : Atenei Parmensis Jul 2022DNA repair systems are functionally essential for the maintenance of life and among these, we can highlight the MutS system, subdivided into MutSα (hMSH2 and hMSH6) and...
BACKGROUND AND AIM
DNA repair systems are functionally essential for the maintenance of life and among these, we can highlight the MutS system, subdivided into MutSα (hMSH2 and hMSH6) and MutSβ (hMSH2 and hMSH3). The objective of this study was to analyze the expression of hMSH2 and hMSH6 repair genes in radiology technicians exposed to low radiation doses.
METHODS
Thirty workers occupationally exposed to ionizing radiation and twenty-five non-exposed were included in this study. Gene expression was analyzed by qPCR. Peripheral blood samples were collected from both groups for total RNA isolation.
RESULTS
It was observed a five-fold increase (p=0.006) in the hMSH2 repair gene expression in those exposed to radiation and a weak but significant correlation (p=0.041) with the hMSH6 genes when we associated the number of hours of exposure with gene expression.
CONCLUSIONS
The longer the exposure time, the greater the activation of this component of the repair system.
APPLICATION TO PRACTICE
Blood count parameters could did not alter with radiation exposure. X-rays used by radiology technicians in imaging tests can damage the DNA to the point of activating the MutS repair system and that there is a greater tendency of expression of this system in professionals that had undergone longer exposure.
Topics: DNA Repair; Humans; Radiation, Ionizing
PubMed: 35775781
DOI: 10.23750/abm.v93i3.12140 -
Nature Reviews. Microbiology Nov 2007The capacity to rectify DNA double-strand breaks (DSBs) is crucial for the survival of all species. DSBs can be repaired either by homologous recombination (HR) or... (Review)
Review
The capacity to rectify DNA double-strand breaks (DSBs) is crucial for the survival of all species. DSBs can be repaired either by homologous recombination (HR) or non-homologous end joining (NHEJ). The long-standing notion that bacteria rely solely on HR for DSB repair has been overturned by evidence that mycobacteria and other genera have an NHEJ system that depends on a dedicated DNA ligase, LigD, and the DNA-end-binding protein Ku. Recent studies have illuminated the role of NHEJ in protecting the bacterial chromosome against DSBs and other clastogenic stresses. There is also emerging evidence of functional crosstalk between bacterial NHEJ proteins and components of other DNA-repair pathways. Although still a young field, bacterial NHEJ promises to teach us a great deal about the nexus of DNA repair and bacterial pathogenesis.
Topics: Bacterial Physiological Phenomena; DNA Breaks, Double-Stranded; DNA Repair; DNA, Bacterial; Recombination, Genetic
PubMed: 17938628
DOI: 10.1038/nrmicro1768 -
Nature Cell Biology Oct 2021
Topics: DNA Breaks; DNA Repair; Genomic Instability; Humans
PubMed: 34616021
DOI: 10.1038/s41556-021-00769-9 -
Human Reproduction Update Mar 2019DNA integrity and stability are critical determinants of cell viability. This is especially true in the female germline, wherein DNA integrity underpins successful...
BACKGROUND
DNA integrity and stability are critical determinants of cell viability. This is especially true in the female germline, wherein DNA integrity underpins successful conception, embryonic development, pregnancy and the production of healthy offspring. However, DNA is not inert; rather, it is subject to assault from various environment factors resulting in chemical modification and/or strand breakage. If structural alterations result and are left unrepaired, they have the potential to cause mutations and propagate disease. In this regard, reduced genetic integrity of the female germline ranks among the leading causes of subfertility in humans. With an estimated 10% of couples in developed countries taking recourse to ART to achieve pregnancy, the need for ongoing research into the capacity of the oocyte to detect DNA damage and thereafter initiate cell cycle arrest, apoptosis or DNA repair is increasingly more pressing.
OBJECTIVE AND RATIONALE
This review documents our current knowledge of the quality control mechanisms utilised by the female germline to prevent and remediate DNA damage during their development from primordial follicles through to the formation of preimplantation embryos.
SEARCH METHODS
The PubMed database was searched using the keywords: primordial follicle, primary follicle, secondary follicle, tertiary follicle, germinal vesical, MI, MII oocyte, zygote, preimplantation embryo, DNA repair, double-strand break and DNA damage. These keywords were combined with other phrases relevant to the topic. Literature was restricted to peer-reviewed original articles in the English language (published 1979-2018) and references within these articles were also searched.
OUTCOMES
In this review, we explore the quality control mechanisms utilised by the female germline to prevent, detect and remediate DNA damage. We follow the trajectory of development from the primordial follicle stage through to the preimplantation embryo, highlighting findings likely to have important implications for fertility management, age-related subfertility and premature ovarian failure. In addition, we survey the latest discoveries regarding DNA repair within the metaphase II (MII) oocyte and implicate maternal stores of endogenous DNA repair proteins and mRNA transcripts as a primary means by which they defend their genomic integrity. The collective evidence reviewed herein demonstrates that the MII oocyte can engage in the activation of major DNA damage repair pathway(s), therefore encouraging a reappraisal of the long-held paradigm that oocytes are largely refractory to DNA repair upon reaching this late stage of their development. It is also demonstrated that the zygote can exploit a number of protective strategies to mitigate the risk and/or effect the repair, of DNA damage sustained to either parental germline; affirming that DNA protection is largely a maternally driven trait but that some aspects of repair may rely on a collaborative effort between the male and female germlines.
WIDER IMPLICATIONS
The present review highlights the vulnerability of the oocyte to DNA damage and presents a number of opportunities for research to bolster the stringency of the oocyte's endogenous defences, with implications extending to improved diagnostics and novel therapeutic applications to alleviate the burden of infertility.
Topics: Blastocyst; DNA Damage; DNA Repair; Embryonic Development; Female; Humans; Infertility; Metaphase; Oocytes; Ovarian Follicle; Pregnancy
PubMed: 30541031
DOI: 10.1093/humupd/dmy040 -
Mammalian Genome : Official Journal of... Aug 2017DNA double-strand breaks (DSBs) are produced intentionally by RNA-guided nucleases to achieve genome editing through DSB repair. These breaks are repaired by one of two... (Review)
Review
DNA double-strand breaks (DSBs) are produced intentionally by RNA-guided nucleases to achieve genome editing through DSB repair. These breaks are repaired by one of two main repair pathways, classic non-homologous end joining (c-NHEJ) and homology-directed repair (HDR), the latter being restricted to the S/G2 phases of the cell cycle and notably less frequent. Precise genome editing applications rely on HDR, with the abundant c-NHEJ formed mutations presenting a barrier to achieving high rates of precise sequence modifications. Here, we give an overview of HDR- and c-NHEJ-mediated DSB repair in gene editing and summarize the current efforts to promote HDR over c-NHEJ.
Topics: Animals; Biomarkers; CRISPR-Cas Systems; DNA End-Joining Repair; DNA Repair; Gene Editing; Gene Knock-In Techniques; Gene Knockout Techniques; Genetic Testing; Homologous Recombination; Humans; Recombinational DNA Repair; Signal Transduction
PubMed: 28374058
DOI: 10.1007/s00335-017-9688-5 -
The Journal of Investigative Dermatology Sep 2003In addition to their established role in repairing post-replicative DNA errors, DNA mismatch repair proteins contribute to cell cycle arrest and apoptosis in response to... (Review)
Review
In addition to their established role in repairing post-replicative DNA errors, DNA mismatch repair proteins contribute to cell cycle arrest and apoptosis in response to a wide range of exogenous DNA damage (e.g., alkylation-induced lesions). The role of DNA mismatch repair in response to ultraviolet-induced DNA damage has been historically controversial. Recent data, however, suggest that DNA mismatch repair proteins probably do not contribute to the removal of ultraviolet-induced DNA damage, but may be important in suppressing mutagenesis, effecting apoptosis, and suppressing tumorigenesis following exposure to ultraviolet radiation.
Topics: Animals; DNA Repair; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Humans; Ultraviolet Rays
PubMed: 12925197
DOI: 10.1046/j.1523-1747.2003.12450.x -
Advances in Genetics 2013A DNA double-strand break (DSB) has long been recognized as a severe cellular lesion, potentially representing an initiating event for carcinogenesis or cell death. The... (Review)
Review
A DNA double-strand break (DSB) has long been recognized as a severe cellular lesion, potentially representing an initiating event for carcinogenesis or cell death. The evolution of DSB repair pathways as well as additional processes, such as cell cycle checkpoint arrest, to minimize the cellular impact of DSB formation was, therefore, not surprising. However, the depth and complexity of the DNA damage responses being revealed by current studies were unexpected. Perhaps the most surprising finding to emerge is the dramatic changes to chromatin architecture that arise in the DSB vicinity. In this review, we overview the cellular response to DSBs focusing on DNA repair pathways and the interface between them. We consider additional events which impact upon these DSB repair pathways, including regulated arrest of cell cycle progression and chromatin architecture alterations. Finally, we discuss the impact of defects in these processes to human disease.
Topics: Animals; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Disease; Humans; Recombination, Genetic; Recombinational DNA Repair; Signal Transduction
PubMed: 23721719
DOI: 10.1016/B978-0-12-407676-1.00001-9 -
Signal Transduction and Targeted Therapy Sep 2020
Review
Topics: Animals; DNA Repair; Genome-Wide Association Study; Humans
PubMed: 32934203
DOI: 10.1038/s41392-020-00314-4 -
Cells Jun 2021Protection of genome integrity is vital for all living organisms, particularly when DNA double-strand breaks (DSBs) occur. Eukaryotes have developed two main pathways,... (Review)
Review
Protection of genome integrity is vital for all living organisms, particularly when DNA double-strand breaks (DSBs) occur. Eukaryotes have developed two main pathways, namely Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR), to repair DSBs. While most of the current research is focused on the role of key protein players in the functional regulation of DSB repair pathways, accumulating evidence has uncovered a novel class of regulating factors termed non-coding RNAs. Non-coding RNAs have been found to hold a pivotal role in the activation of DSB repair mechanisms, thereby safeguarding genomic stability. In particular, long non-coding RNAs (lncRNAs) have begun to emerge as new players with vast therapeutic potential. This review summarizes important advances in the field of lncRNAs, including characterization of recently identified lncRNAs, and their implication in DSB repair pathways in the context of tumorigenesis.
Topics: Animals; DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA End-Joining Repair; DNA Repair; Genomic Instability; Humans; RNA, Long Noncoding; Recombinational DNA Repair
PubMed: 34203749
DOI: 10.3390/cells10061506 -
Clinical Cancer Research : An Official... Dec 2016Drugs targeting DNA damage repair (DDR) pathways are exciting new agents in cancer therapy. Many of these drugs exhibit synthetic lethality with defects in DNA repair in... (Review)
Review
Drugs targeting DNA damage repair (DDR) pathways are exciting new agents in cancer therapy. Many of these drugs exhibit synthetic lethality with defects in DNA repair in cancer cells. For example, ovarian cancers with impaired homologous recombination DNA repair show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Understanding the activity of different DNA repair pathways in individual tumors, and the correlations between DNA repair function and drug response, will be critical to patient selection for DNA repair targeted agents. Genomic and functional assays of DNA repair pathway activity are being investigated as potential biomarkers of response to targeted therapies. Furthermore, alterations in DNA repair function generate resistance to DNA repair targeted agents, and DNA repair states may predict intrinsic or acquired drug resistance. In this review, we provide an overview of DNA repair targeted agents currently in clinical trials and the emerging biomarkers of response and resistance to these agents: genetic and genomic analysis of DDR pathways, genomic signatures of mutational processes, expression of DNA repair proteins, and functional assays for DNA repair capacity. We review biomarkers that may predict response to selected DNA repair targeted agents, including PARP inhibitors, inhibitors of the DNA damage sensors ATM and ATR, and inhibitors of nonhomologous end joining. Finally, we introduce emerging categories of drugs targeting DDR and new strategies for integrating DNA repair targeted therapies into clinical practice, including combination regimens. Generating and validating robust biomarkers will optimize the efficacy of DNA repair targeted therapies and maximize their impact on cancer treatment. Clin Cancer Res; 22(23); 5651-60. ©2016 AACR.
Topics: Antineoplastic Agents; Biomarkers, Tumor; DNA Repair; Drug Resistance, Neoplasm; Humans; Mutation; Neoplasms
PubMed: 27678458
DOI: 10.1158/1078-0432.CCR-16-0247