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Asian Journal of Andrology Jan 2012Among the different DNA anomalies that can be present in the male gamete, DNA fragmentation is the most frequent, particularly in infertile subjects. There is now... (Review)
Review
Among the different DNA anomalies that can be present in the male gamete, DNA fragmentation is the most frequent, particularly in infertile subjects. There is now consistent evidence that a sperm containing fragmented DNA can be alive, motile, morphologically normal and able to fertilize an oocyte. There is also evidence that the oocyte is able to repair DNA damage; however, the extent of this repair depends on the type of DNA damage present in the sperm, as well as on the quality of the oocyte. Thus, it is important to understand the possible consequences of sperm DNA fragmentation (SDF) for embryo development, implantation, pregnancy outcome and the health of progeny conceived, both naturally and by assisted reproductive technology (ART). At present, data on the consequences of SDF for reproduction are scarce and, in many ways, inconsistent. The differences in study conclusions might result from the different methods used to detect SDF, the study design and the inclusion criteria. Consequently, it is difficult to decide whether SDF testing should be carried out in fertility assessment and ART. It is clear that there is an urgent need for the standardisation of the methods and for additional clinical studies on the impact of SDF on ART outcomes.
Topics: Apoptosis; DNA Damage; DNA Fragmentation; Humans; Infertility, Male; Male; Reproductive Techniques, Assisted; Semen Analysis; Spermatozoa
PubMed: 22138903
DOI: 10.1038/aja.2011.59 -
Cell Stem Cell Jan 2011Recent studies have shown that tissue-specific stem cells (SCs) found throughout the body respond differentially to DNA damage. In this review, we will discuss how... (Review)
Review
Recent studies have shown that tissue-specific stem cells (SCs) found throughout the body respond differentially to DNA damage. In this review, we will discuss how different SC populations sense and functionally respond to DNA damage, identify various common and distinct mechanisms utilized by tissue-specific SCs to address DNA damage, and describe how these mechanisms can impact SC genomic integrity by potentially promoting aging, tissue atrophy, and/or cancer development. Finally, we will discuss how similar mechanisms operate in cancer stem cells (CSCs) and can mediate resistance to chemo- and radiotherapy.
Topics: Aging; Animals; DNA Damage; DNA Repair; Humans; Neoplasms; Neoplastic Stem Cells; Signal Transduction
PubMed: 21211780
DOI: 10.1016/j.stem.2010.12.012 -
Mutation Research. Reviews in Mutation... 2016From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation... (Review)
Review
From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations.
Topics: Alkylating Agents; Alkylation; Apoptosis; DNA Adducts; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Humans; Mutagenicity Tests
PubMed: 27036068
DOI: 10.1016/j.mrrev.2015.11.001 -
Cells Jul 2021Many anti-cancer therapeutics lead to the release of danger associated pattern molecules (DAMPs) as the result of killing large numbers of both normal and transformed... (Review)
Review
Many anti-cancer therapeutics lead to the release of danger associated pattern molecules (DAMPs) as the result of killing large numbers of both normal and transformed cells as well as lysis of red blood cells (RBC) (hemolysis). Labile heme originating from hemolysis acts as a DAMP while its breakdown products exert varying immunomodulatory effects. Labile heme is scavenged by hemopexin (Hx) and processed by heme oxygenase-1 (HO-1, ), resulting in its removal and the generation of biliverdin/bilirubin, carbon monoxide (CO) and iron. We recently demonstrated that labile heme accumulates in cancer cell nuclei in the tumor parenchyma of knockout mice and contributes to the malignant phenotype of prostate cancer (PCa) cells and increased metastases. Additionally, this work identified Hx as a tumor suppressor gene. Direct interaction of heme with DNA G-quadruplexes (G4) leads to altered gene expression in cancer cells that regulate transcription, recombination and replication. Here, we provide new data supporting the nuclear role of HO-1 and heme in modulating DNA damage response, G4 stability and cancer growth. Finally, we discuss an alternative role of labile heme as a nuclear danger signal (NDS) that regulates gene expression and nuclear HO-1 regulated DNA damage responses stimulated by its interaction with G4.
Topics: Animals; DNA Damage; G-Quadruplexes; Gene Expression; Gene Expression Regulation; Humans; Immunity; Neoplasms
PubMed: 34359970
DOI: 10.3390/cells10071801 -
Cold Spring Harbor Perspectives in... Jul 2013Under favorable conditions DNA can survive for thousands of years in the remains of dead organisms. The DNA extracted from such remains is invariably degraded to a small... (Review)
Review
Under favorable conditions DNA can survive for thousands of years in the remains of dead organisms. The DNA extracted from such remains is invariably degraded to a small average size by processes that at least partly involve depurination. It also contains large amounts of deaminated cytosine residues that are accumulated toward the ends of the molecules, as well as several other lesions that are less well characterized.
Topics: DNA; DNA Damage; DNA Fragmentation; Deamination; Sequence Analysis, DNA; Time Factors
PubMed: 23729639
DOI: 10.1101/cshperspect.a012567 -
Proceedings of the National Academy of... Jun 2023Understanding and predicting the outcome of the interaction of light with DNA has a significant impact on the study of DNA repair and radiotherapy. We report on a...
Understanding and predicting the outcome of the interaction of light with DNA has a significant impact on the study of DNA repair and radiotherapy. We report on a combination of femtosecond pulsed laser microirradiation at different wavelengths, quantitative imaging, and numerical modeling that yields a comprehensive picture of photon-mediated and free-electron-mediated DNA damage pathways in live cells. Laser irradiation was performed under highly standardized conditions at four wavelengths between 515 nm and 1,030 nm, enabling to study two-photon photochemical and free-electron-mediated DNA damage in situ. We quantitatively assessed cyclobutane pyrimidine dimer (CPD) and γH2AX-specific immunofluorescence signals to calibrate the damage threshold dose at these wavelengths and performed a comparative analysis of the recruitment of DNA repair factors xeroderma pigmentosum complementation group C (XPC) and Nijmegen breakage syndrome 1 (Nbs1). Our results show that two-photon-induced photochemical CPD generation dominates at 515 nm, while electron-mediated damage dominates at wavelengths ≥620 nm. The recruitment analysis revealed a cross talk between nucleotide excision and homologous recombination DNA repair pathways at 515 nm. Numerical simulations predicted electron densities and electron energy spectra, which govern the yield functions of a variety of direct electron-mediated DNA damage pathways and of indirect damage by OH radicals resulting from laser and electron interactions with water. Combining these data with information on free electron-DNA interactions gained in artificial systems, we provide a conceptual framework for the interpretation of the wavelength dependence of laser-induced DNA damage that may guide the selection of irradiation parameters in studies and applications that require the selective induction of DNA lesions.
Topics: Electrons; DNA Damage; Pyrimidine Dimers; DNA Repair; Lasers
PubMed: 37307476
DOI: 10.1073/pnas.2220132120 -
Future Oncology (London, England) Feb 2013The cellular reaction to genomic instability includes a network of signal transduction pathways collectively referred to as the DNA damage response (DDR). Activated by a... (Review)
Review
The cellular reaction to genomic instability includes a network of signal transduction pathways collectively referred to as the DNA damage response (DDR). Activated by a variety of DNA lesions, the DDR orchestrates cell cycle arrest and DNA repair, and initiates apoptosis in instances where damage cannot be repaired. As such, disruption of the DDR increases the prevalence of DNA damage secondary to incomplete repair, and in doing so, enhances radiation-induced cytotoxicity. This article describes the molecular agents and their targets within DDR pathways that sensitize cells to radiation. Moreover, it reviews the therapeutic implications of these compounds, provides an overview of relevant clinical trials and offers a viewpoint on the evolution of the field in the years to come.
Topics: Animals; DNA Damage; Humans; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction
PubMed: 23414472
DOI: 10.2217/fon.12.185 -
Cold Spring Harbor Perspectives in... Jun 2013Alternative excision repair (AER) is a category of excision repair initiated by a single nick, made by an endonuclease, near the site of DNA damage, and followed by... (Review)
Review
Alternative excision repair (AER) is a category of excision repair initiated by a single nick, made by an endonuclease, near the site of DNA damage, and followed by excision of the damaged DNA, repair synthesis, and ligation. The ultraviolet (UV) damage endonuclease in fungi and bacteria introduces a nick immediately 5' to various types of UV damage and initiates its excision repair that is independent of nucleotide excision repair (NER). Endo IV-type apurinic/apyrimidinic (AP) endonucleases from Escherichia coli and yeast and human Exo III-type AP endonuclease APEX1 introduce a nick directly and immediately 5' to various types of oxidative base damage besides the AP site, initiating excision repair. Another endonuclease, endonuclease V from bacteria to humans, binds deaminated bases and cleaves the phosphodiester bond located 1 nucleotide 3' of the base, leading to excision repair. A single-strand break in DNA is one of the most frequent types of DNA damage within cells and is repaired efficiently. AER makes use of such repair capability of single-strand breaks, removes DNA damage, and has an important role in complementing BER and NER.
Topics: Animals; DNA Breaks, Single-Stranded; DNA Damage; DNA Repair; DNA Repair Enzymes; Endonucleases; Humans; Models, Biological; Species Specificity; Yeasts
PubMed: 23645854
DOI: 10.1101/cshperspect.a012617 -
Wiley Interdisciplinary Reviews. RNA 2010The cellular DNA damage response (DDR) involves changes in the functional and structural properties of a number of nuclear proteins, resulting in a coordinated control... (Review)
Review
The cellular DNA damage response (DDR) involves changes in the functional and structural properties of a number of nuclear proteins, resulting in a coordinated control of gene expression and DNA repair. This response includes functional interactions of the DNA repair, transcription, and RNA processing machineries. Following DNA damage, cellular levels of polyadenylated transcripts are transiently decreased and normal recovery depends on transcription-coupled repair (TCR). In addition, DNA damage has gene-specific effects regulating the mRNA levels of factors involved in the DDR itself at different times after the damage. The 3'-end processing machinery, which is important in the regulation of mRNA stability, is involved in these general and gene-specific responses to DNA damage. The role of 3'-end processing in DDR supports the idea that the steady-state levels of different mRNAs change upon DNA-damaging conditions as a result of regulation of not only their biosynthesis but also their turnover. Here, we review the mechanistic connections between 3'-end processing and DDR, and discuss the implications of deregulation of this important step of mRNA maturation in the cellular recovery after DNA-damaging treatment. The relevance of these functional connections is illustrated by the increasing number of reports on this relatively unexplored field.
Topics: Animals; DNA Damage; DNA Repair; Gene Expression Regulation; Humans; Models, Biological; RNA 3' End Processing; RNA, Messenger
PubMed: 21956914
DOI: 10.1002/wrna.20 -
DNA Repair Aug 2023DNA adducts and strand breaks are induced by various exogenous and endogenous agents. Accumulation of DNA damage is implicated in many disease processes, including... (Review)
Review
DNA adducts and strand breaks are induced by various exogenous and endogenous agents. Accumulation of DNA damage is implicated in many disease processes, including cancer, aging, and neurodegeneration. The continuous acquisition of DNA damage from exogenous and endogenous stressors coupled with defects in DNA repair pathways contribute to the accumulation of DNA damage within the genome and genomic instability. While mutational burden offers some insight into the level of DNA damage a cell may have experienced and subsequently repaired, it does not quantify DNA adducts and strand breaks. Mutational burden also infers the identity of the DNA damage. With advances in DNA adduct detection and quantification methods, there is an opportunity to identify DNA adducts driving mutagenesis and correlate with a known exposome. However, most DNA adduct detection methods require isolation or separation of the DNA and its adducts from the context of the nuclei. Mass spectrometry, comet assays, and other techniques precisely quantify lesion types but lose the nuclear context and even tissue context of the DNA damage. The growth in spatial analysis technologies offers a novel opportunity to leverage DNA damage detection with nuclear and tissue context. However, we lack a wealth of techniques capable of detecting DNA damage in situ. Here, we review the limited existing in situ DNA damage detection methods and examine their potential to offer spatial analysis of DNA adducts in tumors or other tissues. We also offer a perspective on the need for spatial analysis of DNA damage in situ and highlight Repair Assisted Damage Detection (RADD) as an in situ DNA adduct technique with the potential to integrate with spatial analysis and the challenges to be addressed.
Topics: Humans; DNA Adducts; DNA Damage; DNA Repair; Mutagenesis; Neoplasms
PubMed: 37390674
DOI: 10.1016/j.dnarep.2023.103529