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Advances in Protein Chemistry and... 2019Previously, DNA damage sensing, repairing and signaling machineries were thought to mainly suppress genomic instability in response to genotoxic stress. Emerging... (Review)
Review
Previously, DNA damage sensing, repairing and signaling machineries were thought to mainly suppress genomic instability in response to genotoxic stress. Emerging evidence indicates a crosstalk between DNA repair machinery and the immune system. In this chapter, we attempt to decipher the molecular choreography of how factors, including ATM, BRCA1, DNA-PK, FANCA/D2, MRE11, MUS81, NBS1, RAD51 and TREX1, of multiple DNA metabolic processes are directly or indirectly involved in suppressing cytosolic DNA sensing pathway-mediated immune signaling. We provide systematic details showing how different DDR factors' roles in modulating immune signaling are not direct, but are rather a consequence of their inherent ability to sense, repair and signal in response to DNA damage. Unexpectedly, most DDR factors negatively impact the immune system; that is, the immune system shows defective signaling if there are defects in DNA repair pathways. Thus, in addition to their known DNA repair and replication functions, DDR factors help prevent erroneous activation of immune signaling. A more precise understanding of the mechanisms by which different DDR factors function in immune signaling can be exploited to redirect the immune system for both preventing and treating autoimmunity, cellular senescence and cancer in humans.
Topics: DNA; DNA Damage; DNA Repair; Humans; Signal Transduction
PubMed: 30798935
DOI: 10.1016/bs.apcsb.2018.11.004 -
Molecules (Basel, Switzerland) Dec 2020The production of haploid gametes through meiosis is central to the principle of sexual reproduction. The genetic diversity is further enhanced by exchange of genetic... (Review)
Review
The production of haploid gametes through meiosis is central to the principle of sexual reproduction. The genetic diversity is further enhanced by exchange of genetic material between homologous chromosomes by the crossover mechanism. This mechanism not only requires correct pairing of homologous chromosomes but also efficient repair of the induced DNA double-strand breaks. Oocytes have evolved a unique quality control system that eliminates cells if chromosomes do not correctly align or if DNA repair is not possible. Central to this monitoring system that is conserved from nematodes and fruit fly to humans is the p53 protein family, and in vertebrates in particular p63. In mammals, oocytes are stored for a long time in the prophase of meiosis I which, in humans, can last more than 50 years. During the entire time of this arrest phase, the DNA damage checkpoint remains active. The treatment of female cancer patients with DNA damaging irradiation or chemotherapeutics activates this checkpoint and results in elimination of the oocyte pool causing premature menopause and infertility. Here, we review the molecular mechanisms of this quality control system and discuss potential therapeutic intervention for the preservation of the oocyte pool during chemotherapy.
Topics: Animals; Cell Death; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Humans; Oocytes
PubMed: 33287328
DOI: 10.3390/molecules25235714 -
Molecular Biology Reports Dec 2022Damage-specific DNA-binding protein 2 (DDB2) was initially identified as a component of the damage-specific DNA-binding heterodimeric complex, which cooperates with... (Review)
Review
Damage-specific DNA-binding protein 2 (DDB2) was initially identified as a component of the damage-specific DNA-binding heterodimeric complex, which cooperates with other proteins to repair UV-induced DNA damage. DDB2 is involved in the occurrence and development of cancer by affecting nucleotide excision repair (NER), cell apoptosis, and premature senescence. DDB2 also affects the sensitivity of cancer cells to radiotherapy and chemotherapy. In addition, a recent study found that DDB2 is a pathogenic gene for hepatitis and encephalitis. In recent years, there have been few relevant literature reports on DDB2, so there is still room for further research about it. In this paper, the molecular mechanisms of different biological processes involving DDB2 are reviewed in detail to provide theoretical support for research on drugs that can target DDB2.
Topics: Ultraviolet Rays; DNA Repair; DNA-Binding Proteins; DNA Damage; Apoptosis
PubMed: 36190612
DOI: 10.1007/s11033-022-07963-4 -
Genes Dec 2022Double-strand breaks (DSBs) are toxic lesions that can be generated by exposure to genotoxic agents or during physiological processes, such as during V(D)J... (Review)
Review
Double-strand breaks (DSBs) are toxic lesions that can be generated by exposure to genotoxic agents or during physiological processes, such as during V(D)J recombination. The repair of these DSBs is crucial to prevent genomic instability and to maintain cellular homeostasis. Two main pathways participate in repairing DSBs, namely, non-homologous end joining (NHEJ) and homologous recombination (HR). The P53-binding protein 1 (53BP1) plays a pivotal role in the choice of DSB repair mechanism, promotes checkpoint activation and preserves genome stability upon DSBs. By preventing DSB end resection, 53BP1 promotes NHEJ over HR. Nonetheless, the balance between DSB repair pathways remains crucial, as unscheduled NHEJ or HR events at different phases of the cell cycle may lead to genomic instability. Therefore, the recruitment of 53BP1 to chromatin is tightly regulated and has been widely studied. However, less is known about the mechanism regulating 53BP1 recruitment at a distance from the DNA damage. The present review focuses on the mechanism of 53BP1 recruitment to damage and on recent studies describing novel mechanisms keeping 53BP1 at a distance from DSBs.
Topics: Humans; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Damage; Chromatin; Genomic Instability
PubMed: 36553657
DOI: 10.3390/genes13122390 -
The International Journal of... 2016In response to a variety of DNA replication stress or DNA damaging agents, the DNA damage response (DDR) pathways are triggered for cells to coordinate DNA repair, cell... (Review)
Review
In response to a variety of DNA replication stress or DNA damaging agents, the DNA damage response (DDR) pathways are triggered for cells to coordinate DNA repair, cell cycle checkpoints, apoptosis, and senescence. Cell-free Xenopus egg extracts, derived from the eggs of African clawed frogs (Xenopus laevis), have been widely used for studies concerning DDR pathways. In this review, we focus on how different experimental systems have been established using Xenopus egg extracts to investigate the DDR pathways that are activated in response to DNA replication stress, double-strand breaks (DSBs), inter-strand crosslinks (ICLs), and oxidative stress. We summarize how molecular details of DDR pathways are dissected by the mechanistic studies with Xenopus egg extracts. We also provide an update on the regulation of translesion DNA synthesis (TLS) polymerases (Pol ĸ and REV1) in the DDR pathways. A better understanding of DDR pathways using Xenopus egg extracts has opened new avenues for future cancer therapeutics. Finally, we offer our perspectives of future directions for studies of DDR pathways with Xenopus egg extracts.
Topics: Animals; Apoptosis; Cell-Free System; Cellular Senescence; DNA Damage; Oocytes; Xenopus
PubMed: 27160070
DOI: 10.1387/ijdb.160113sy -
The FEBS Journal Jul 2016Cellular senescence is a complex stress response that leads to an irreversible state of cell growth arrest. Senescence may be induced by various stimuli such as telomere... (Review)
Review
Cellular senescence is a complex stress response that leads to an irreversible state of cell growth arrest. Senescence may be induced by various stimuli such as telomere shortening, DNA damage or oncogenic insult, among others. Senescent cells are metabolically highly active, producing a wealth of cytokines and chemokines that, depending on the context, may have a beneficial or deleterious effect on the organism. Senescence is considered a tightly regulated stress response that is largely governed by the p53/p21 and p16/Rb pathways. Many molecules have been identified as regulators of these two networks, such as transcription factors, chromatin modifiers and non-coding RNAs. The expression level of several long non-coding RNAs is affected during different types of senescence; however, which of these are important for the biological function remains poorly understood. Here we review our current knowledge of the mechanistic roles of lncRNAs affecting the main senescence pathways, and discuss the importance of identifying new regulators.
Topics: Animals; Cellular Senescence; DNA Damage; Humans; Models, Biological; RNA, Long Noncoding; Signal Transduction
PubMed: 26866709
DOI: 10.1111/febs.13679 -
Experimental Cell Research Nov 2014DNA replication is a fundamental process of the cell that ensures accurate duplication of the genetic information and subsequent transfer to daughter cells. Various... (Review)
Review
DNA replication is a fundamental process of the cell that ensures accurate duplication of the genetic information and subsequent transfer to daughter cells. Various pertubations, originating from endogenous or exogenous sources, can interfere with proper progression and completion of the replication process, thus threatening genome integrity. Coordinated regulation of replication and the DNA damage response is therefore fundamental to counteract these challenges and ensure accurate synthesis of the genetic material under conditions of replication stress. In this review, we summarize the main sources of replication stress and the DNA damage signaling pathways that are activated in order to preserve genome integrity during DNA replication. We also discuss the association of replication stress and DNA damage in human disease and future perspectives in the field.
Topics: Animals; DNA Damage; DNA Replication; Disease; Genomic Instability; Humans
PubMed: 25281304
DOI: 10.1016/j.yexcr.2014.09.030 -
Human Genetics Mar 2020DNA damage is one of the most consistent cellular process proposed to contribute to aging. The maintenance of genomic and epigenomic integrity is critical for proper... (Review)
Review
DNA damage is one of the most consistent cellular process proposed to contribute to aging. The maintenance of genomic and epigenomic integrity is critical for proper function of cells and tissues throughout life, and this homeostasis is under constant strain from both extrinsic and intrinsic insults. Considering the relationship between lifespan and genotoxic burden, it is plausible that the longest-lived cellular populations would face an accumulation of DNA damage over time. Tissue-specific stem cells are multipotent populations residing in localized niches and are responsible for maintaining all lineages of their resident tissue/system throughout life. However, many of these stem cells are impacted by genotoxic stress. Several factors may dictate the specific stem cell population response to DNA damage, including the niche location, life history, and fate decisions after damage accrual. This leads to differential handling of DNA damage in different stem cell compartments. Given the importance of adult stem cells in preserving normal tissue function during an individual's lifetime, DNA damage sensitivity and accumulation in these compartments could have crucial implications for aging. Despite this, more support for direct functional effects driven by accumulated DNA damage in adult stem cell compartments is needed. This review will present current evidence for the accumulation and potential influence of DNA damage in adult tissue-specific stem cells and propose inquiry directions that could benefit individual healthspan.
Topics: Aging; Animals; DNA Damage; Homeostasis; Humans; Stem Cells
PubMed: 31324975
DOI: 10.1007/s00439-019-02047-z -
Ageing Research Reviews Sep 2015The maintenance of the genome is of pivotal importance for the functional integrity of cells and tissues. The gradual accumulation of DNA damage is thought to contribute... (Review)
Review
The maintenance of the genome is of pivotal importance for the functional integrity of cells and tissues. The gradual accumulation of DNA damage is thought to contribute to the functional decline of tissues and organs with ageing. Defects in multiple genome maintenance systems cause human disorders characterized by cancer susceptibility, developmental failure, and premature ageing. The complex pathological consequences of genome instability are insufficiently explained by cell-autonomous DNA damage responses (DDR) alone. Quality control pathways play an important role in DNA repair and cellular DDR pathways. Recent years have revealed non-cell autonomous effects of DNA damage that impact the physiological adaptations during ageing. We will discuss the role of quality assurance pathways in cell-autonomous and systemic responses to genome instability.
Topics: Aging; Animals; Cell Nucleus; DNA Damage; Genome, Human; Genomic Instability; Humans; Protein Biosynthesis; Quality Control
PubMed: 25560147
DOI: 10.1016/j.arr.2014.12.009 -
Biomolecules Oct 2015Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery,... (Review)
Review
Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and DNA repair. Cells respond to DNA damage by activating complex DNA damage response (DDR) pathways that include: (i) cell cycle arrest; (ii) transcriptional and post-translational activation of a subset of genes, including those associated with DNA repair; and (iii) triggering of programmed cell death. The efficacy of the DDR pathways is influenced by the nuclear levels of DNA repair proteins, which are regulated by balancing between protein synthesis and degradation as well as by nuclear import and export. The inability to respond properly to either DNA damage or to DNA repair leads to genetic instability, which in turn may enhance the rate of cancer development. Multiple components of the DNA double strand breaks repair machinery, including BRCA1, BRCA2, CHK1, DNA-PKcs, FANCA, and the MRE11/RAD50/NBN complex, have been described to be client proteins of Hsp90, which acts as a regulator of the diverse DDR pathways. Inhibition of Hsp90 actions leads to the altered localization and stabilization of DDR proteins after DNA damage and may represent a cell-specific and tumor-selective radiosensibilizer. Here, the role of Hsp90-dependent molecular mechanisms involved in cancer onset and in the maintenance of the genome integrity is discussed and highlighted.
Topics: DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; HSP90 Heat-Shock Proteins; Humans
PubMed: 26501335
DOI: 10.3390/biom5042589