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Blood Jun 2022
Topics: Chromatin Assembly and Disassembly; DNA Repair; Epigenesis, Genetic; Epigenome
PubMed: 35679076
DOI: 10.1182/blood.2022016176 -
International Journal of Molecular... Feb 2021DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage. In humans, DSBs are repaired mainly by non-homologous end joining (NHEJ) and homologous... (Review)
Review
DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage. In humans, DSBs are repaired mainly by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Single-strand annealing (SSA), another DSB repair system, uses homologous repeats flanking a DSB to join DNA ends and is error-prone, as it removes DNA fragments between repeats along with one repeat. Many DNA deletions observed in cancer cells display homology at breakpoint junctions, suggesting the involvement of SSA. When multiple DSBs occur in different chromosomes, SSA may result in chromosomal translocations, essential in the pathogenesis of many cancers. Inhibition of RAD52 (RAD52 Homolog, DNA Repair Protein), the master regulator of SSA, results in decreased proliferation of BRCA1/2 (BRCA1/2 DNA Repair Associated)-deficient cells, occurring in many hereditary breast and ovarian cancer cases. Therefore, RAD52 may be targeted in synthetic lethality in cancer. SSA may modulate the response to platinum-based anticancer drugs and radiation. SSA may increase the efficacy of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR associated 9) genome editing and reduce its off-target effect. Several basic problems associated with SSA, including its evolutionary role, interplay with HRR and NHEJ and should be addressed to better understand its role in cancer pathogenesis and therapy.
Topics: BRCA1 Protein; BRCA2 Protein; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Breaks, Double-Stranded; DNA Repair; DNA, Single-Stranded; Female; Gene Editing; Genomic Instability; Humans; Neoplasms
PubMed: 33671579
DOI: 10.3390/ijms22042167 -
Genes Jun 2022Research studies regarding synthetic lethality (SL) in human cells are primarily motivated by the potential of this phenomenon to be an effective, but at the same time,... (Review)
Review
Research studies regarding synthetic lethality (SL) in human cells are primarily motivated by the potential of this phenomenon to be an effective, but at the same time, safe to the patient's anti-cancer chemotherapy. Among the factors that are targets for the induction of the synthetic lethality effect, those involved in DNA repair seem to be the most relevant. Specifically, when mutation in one of the canonical DNA double-strand break (DSB) repair pathways occurs, which is a frequent event in cancer cells, the alternative pathways may be a promising target for the elimination of abnormal cells. Currently, inhibiting RAD52 and/or PARP1 in the tumor cells that are deficient in the canonical repair pathways has been the potential target for inducing the effect of synthetic lethality. Unfortunately, the development of resistance to commonly used PARP1 inhibitors (PARPi) represents the greatest obstacle to working out a successful treatment protocol. DNA polymerase theta (Polθ), encoded by the POLQ gene, plays a key role in an alternative DSB repair pathway-theta-mediated end joining (TMEJ). Thus, it is a promising target in the treatment of tumors harboring deficiencies in homologous recombination repair (HRR), where its inhibition can induce SL. In this review, the authors discuss the current state of knowledge on Polθ as a potential target for synthetic lethality-based anticancer therapies.
Topics: DNA Breaks, Double-Stranded; DNA Repair; Humans; Neoplasms; Recombinational DNA Repair; Synthetic Lethal Mutations
PubMed: 35741863
DOI: 10.3390/genes13061101 -
International Journal of Molecular... Apr 2022Neurological complications directly impact the lives of hundreds of millions of people worldwide. While the precise molecular mechanisms that underlie neuronal cell loss... (Review)
Review
Neurological complications directly impact the lives of hundreds of millions of people worldwide. While the precise molecular mechanisms that underlie neuronal cell loss remain under debate, evidence indicates that the accumulation of genomic DNA damage and consequent cellular responses can promote apoptosis and neurodegenerative disease. This idea is supported by the fact that individuals who harbor pathogenic mutations in DNA damage response genes experience profound neuropathological manifestations. The review article here provides a general overview of the nervous system, the threats to DNA stability, and the mechanisms that protect genomic integrity while highlighting the connections of DNA repair defects to neurological disease. The information presented should serve as a prelude to the Special Issue "Genome Stability and Neurological Disease", where experts discuss the role of DNA repair in preserving central nervous system function in greater depth.
Topics: DNA Damage; DNA Repair; Genome; Genomic Instability; Humans; Neurodegenerative Diseases
PubMed: 35456958
DOI: 10.3390/ijms23084142 -
Molecular Cell Oct 2023In recent years, increasing evidence has highlighted the profound connection between DNA damage repair and the activation of immune responses. We spoke with researchers...
In recent years, increasing evidence has highlighted the profound connection between DNA damage repair and the activation of immune responses. We spoke with researchers about their mechanistic interplays and the implications for cancer and other diseases.
Topics: DNA Damage; DNA Repair; Signal Transduction; Immunity
PubMed: 37863025
DOI: 10.1016/j.molcel.2023.09.022 -
DNA Repair Jan 2022The genomic DNA is constantly under attack by cellular and/or environmental factors. Fortunately, the cell is armed to safeguard its genome by various mechanisms such as... (Review)
Review
The genomic DNA is constantly under attack by cellular and/or environmental factors. Fortunately, the cell is armed to safeguard its genome by various mechanisms such as nucleotide excision, base excision, mismatch and DNA double-strand break repairs. While these processes maintain the integrity of the genome throughout, DNA repair occurs preferentially faster at the transcriptionally active genes. Such transcription-coupled repair phenomenon plays important roles to maintain active genome integrity, failure of which would interfere with transcription, leading to an altered gene expression (and hence cellular pathologies/diseases). Among the various DNA damages, DNA double-strand breaks are quite toxic to the cells. If DNA double-strand break occurs at the active gene, it would interfere with transcription/gene expression, thus threatening cellular viability. Such DNA double-strand breaks are found to be repaired faster at the active gene in comparison to its inactive state or the inactive gene, thus supporting the existence of a new phenomenon of transcription-coupled DNA double-strand break repair. Here, we describe the advances of this repair process.
Topics: DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Eukaryota; Humans; Recombinational DNA Repair; Transcription, Genetic
PubMed: 34883263
DOI: 10.1016/j.dnarep.2021.103211 -
Advances in Experimental Medicine and... 2022Growth arrest and DNA damage 45 (Gadd45) family genes, Gadd45A, Gadd45B, and GADD45 G are implicated as stress sensors that are rapidly induced upon...
Growth arrest and DNA damage 45 (Gadd45) family genes, Gadd45A, Gadd45B, and GADD45 G are implicated as stress sensors that are rapidly induced upon genotoxic/physiological stress. They are involved in regulation of various cellular functions such as DNA repair, senescence, and cell cycle control. Gadd45 family of genes serve as tumor suppressors in response to different stimuli and defects in Gadd45 pathway can give rise to oncogenesis. More recently, Gadd45 has been shown to promote gene activation by demethylation and this function is important for transcriptional regulation and differentiation during development. Gadd45 serves as an adaptor for DNA repair factors to promote removal of 5-methylcytosine from DNA at gene specific loci. Therefore, Gadd45 serves as a powerful link between DNA repair and epigenetic gene regulation.
Topics: Cell Cycle Checkpoints; Cell Cycle Proteins; DNA Damage; DNA Demethylation; DNA Repair
PubMed: 35505162
DOI: 10.1007/978-3-030-94804-7_4 -
Microbiology and Molecular Biology... Dec 2021Staphylococcus aureus is a common cause of both superficial and invasive infections of humans and animals. Despite a potent host response and apparently appropriate... (Review)
Review
Staphylococcus aureus is a common cause of both superficial and invasive infections of humans and animals. Despite a potent host response and apparently appropriate antibiotic therapy, staphylococcal infections frequently become chronic or recurrent, demonstrating a remarkable ability of S. aureus to withstand the hostile host environment. There is growing evidence that staphylococcal DNA repair makes important contributions to the survival of the pathogen in host tissues, as well as promoting the emergence of mutants that resist host defenses and antibiotics. While much of what we know about DNA repair in S. aureus is inferred from studies with model organisms, the roles of specific repair mechanisms in infection are becoming clear and differences with Bacillus subtilis and Escherichia coli have been identified. Furthermore, there is growing interest in staphylococcal DNA repair as a target for novel therapeutics that sensitize the pathogen to host defenses and antibiotics. In this review, we discuss what is known about staphylococcal DNA repair and its role in infection, examine how repair in S. aureus is similar to, or differs from, repair in well-characterized model organisms, and assess the potential of staphylococcal DNA repair as a novel therapeutic target.
Topics: Animals; Anti-Bacterial Agents; DNA Repair; Humans; Staphylococcal Infections; Staphylococcus aureus
PubMed: 34523959
DOI: 10.1128/MMBR.00091-21 -
Cancer Journal (Sudbury, Mass.)DNA damage response and repair (DDR) is responsible for ensuring genomic integrity. It is composed of intricate, complex pathways that detect various DNA insults and... (Review)
Review
DNA damage response and repair (DDR) is responsible for ensuring genomic integrity. It is composed of intricate, complex pathways that detect various DNA insults and then activate pathways to restore DNA fidelity. Mutations in this network are implicated in many malignancies but can also be exploited for cancer therapies. The advent of inhibitors of poly(ADP-ribose) polymerase has led to the investigation of other DDR inhibitors and combinations to address high unmet needs in cancer therapeutics. Specifically, regimens, often in combination with chemotherapy, radiation, or other DDR inhibitors, are being investigated. This review will focus on 4 main DDR pathways-ATR/CHK1, ATM/CHK2, DNA-PKcs, and polymerase θ-and the current state of clinical research and use of the inhibitors of these pathways with other DDR inhibitors.
Topics: Combined Modality Therapy; DNA Damage; DNA Repair; Humans; Mutation; Neoplasms
PubMed: 34904813
DOI: 10.1097/PPO.0000000000000561 -
Seminars in Cancer Biology Oct 2022The acquisition of DNA damage is an early driving event in tumorigenesis. Premalignant lesions show activated DNA damage responses and inactivation of DNA damage... (Review)
Review
The acquisition of DNA damage is an early driving event in tumorigenesis. Premalignant lesions show activated DNA damage responses and inactivation of DNA damage checkpoints promotes malignant transformation. However, DNA damage is also a targetable vulnerability in cancer cells. This requires a detailed understanding of the cellular and molecular mechanisms governing DNA integrity. Here, we review current work on DNA damage in tumorigenesis. We discuss DNA double strand break repair, how repair pathways contribute to tumorigenesis, and how double strand breaks are linked to the tumor microenvironment. Next, we discuss the role of oncogenes in promoting DNA damage through replication stress. Finally, we discuss our current understanding on DNA damage in micronuclei and discuss therapies targeting these DNA damage pathways.
Topics: Humans; DNA Repair; DNA Damage; DNA Breaks, Double-Stranded; Cell Transformation, Neoplastic; DNA; Genomic Instability; Tumor Microenvironment
PubMed: 33905873
DOI: 10.1016/j.semcancer.2021.04.012