-
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 -
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 -
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 -
The Journal of Biological Chemistry Apr 2015In a previous autobiographical sketch for DNA Repair (Linn, S. (2012) Life in the serendipitous lane: excitement and gratification in studying DNA repair. DNA Repair 11,...
In a previous autobiographical sketch for DNA Repair (Linn, S. (2012) Life in the serendipitous lane: excitement and gratification in studying DNA repair. DNA Repair 11, 595-605), I wrote about my involvement in research on mechanisms of DNA repair. In this Reflections, I look back at how I became interested in free radical chemistry and biology and outline some of our bizarre (at the time) observations. Of course, these studies could never have succeeded without the exceptional aid of my mentors: my teachers; the undergraduate and graduate students, postdoctoral fellows, and senior lab visitors in my laboratory; and my faculty and staff colleagues here at Berkeley. I am so indebted to each and every one of these individuals for their efforts to overcome my ignorance and set me on the straight and narrow path to success in research. I regret that I cannot mention and thank each of these mentors individually.
Topics: California; DNA Repair; Mentors
PubMed: 25713083
DOI: 10.1074/jbc.X115.644989 -
Mechanisms of Ageing and Development Jul 2017The presence of damaged and microbial DNA can pose a threat to the survival of organisms. Cells express various sensors that recognize specific aspects of such... (Review)
Review
The presence of damaged and microbial DNA can pose a threat to the survival of organisms. Cells express various sensors that recognize specific aspects of such potentially dangerous DNA. Recognition of damaged or microbial DNA by sensors induces cellular processes that are important for DNA repair and inflammation. Here, we review recent evidence that the cellular response to DNA damage and microbial DNA are tightly intertwined. We also discuss insights into the parameters that enable DNA sensors to distinguish damaged and microbial DNA from DNA present in healthy cells.
Topics: Animals; Bacteria; DNA Repair; DNA, Bacterial; Humans; Inflammation
PubMed: 27614000
DOI: 10.1016/j.mad.2016.09.001 -
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 -
Current Opinion in Genetics &... Dec 2021Helicases are in the spotlight of DNA metabolism and are critical for DNA repair in all domains of life. At their biochemical core, they bind and hydrolyze ATP,... (Review)
Review
Helicases are in the spotlight of DNA metabolism and are critical for DNA repair in all domains of life. At their biochemical core, they bind and hydrolyze ATP, converting this energy to translocate unidirectionally, with different strand polarities and substrate binding specificities, along one strand of a nucleic acid. In doing so, DNA and RNA helicases separate duplex strands or remove nucleoprotein complexes, affecting DNA repair and the architecture of replication forks. In this review, we focus on recent advances on the roles and regulations of DNA helicases in homologous recombination repair, a critical pathway for mending damaged chromosomes and for ensuring genome integrity.
Topics: DNA Damage; DNA Helicases; DNA Repair; DNA Replication; Homologous Recombination; Recombinational DNA Repair
PubMed: 34271541
DOI: 10.1016/j.gde.2021.06.009 -
Trends in Molecular Medicine Sep 2021Progeroid syndromes (PSs) are characterized by the premature onset of age-related pathologies. The genetic mutations underlying PSs are functionally linked to genome... (Review)
Review
Progeroid syndromes (PSs) are characterized by the premature onset of age-related pathologies. The genetic mutations underlying PSs are functionally linked to genome maintenance and repair, supporting the causative role of DNA damage accumulation in aging. Recent advances from studies in animal models of PSs have provided new insight into the role of DNA repair mechanisms in human disease and the physiological adaptations to accumulating DNA damage during aging. The molecular pathology of PSs is reminiscent of the natural aging process, highlighting the relevance for a wide range of age-related diseases. Recent progress has led to the development of novel therapeutic strategies against age-related diseases that are relevant to rare diseases as well as the general aging population.
Topics: Aged; Aging; Aging, Premature; Animals; DNA Damage; DNA Repair; Humans; Pathology, Molecular; Rare Diseases
PubMed: 34272172
DOI: 10.1016/j.molmed.2021.06.011 -
The Journal of Clinical Investigation Oct 2018A complex DNA repair machinery has evolved to protect genomic integrity in the face of a myriad of DNA damage sources. When DNA repair fails, this damage can lead to... (Review)
Review
A complex DNA repair machinery has evolved to protect genomic integrity in the face of a myriad of DNA damage sources. When DNA repair fails, this damage can lead to carcinogenesis and tumor genomic instability. Indeed, many heritable cancer predisposition syndromes are attributable to germline defects in DNA repair pathways. On the other hand, these defects may also portend particular vulnerabilities of the cancer and may be exploited therapeutically. Most recently this has been demonstrated in the case of mismatch repair-deficient cancers, in which the immune checkpoint inhibitors have been demonstrated to be highly active. This observation has paved the way for further research investigating other sources of genomic instability that may serve as biomarkers to select patients for immunotherapy.
Topics: DNA Damage; DNA Repair; Genomic Instability; Humans; Immunotherapy; Neoplasms
PubMed: 30272580
DOI: 10.1172/JCI122010