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Signal Transduction and Targeted Therapy Sep 2023Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance of genome integrity... (Review)
Review
Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance of genome integrity in cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting DDR processes could induce excessive DNA damages (or unrepaired DNA) that eventually lead to cell death. Poly (ADP-ribose) polymerase (PARP) inhibitors have brought impressive benefit to patients with breast cancer gene (BRCA) mutation or homologous recombination deficiency (HRD), which proves the concept of synthetic lethality in cancer treatment. Moreover, the other two scenarios of DDR inhibitor application, replication stress and combination with chemo- or radio- therapy, are under active clinical exploration. In this review, we revisited the progress of DDR targeting therapy beyond the launched first-generation PARP inhibitors. Next generation PARP1 selective inhibitors, which could maintain the efficacy while mitigating side effects, may diversify the application scenarios of PARP inhibitor in clinic. Albeit with unavoidable on-mechanism toxicities, several small molecules targeting DNA damage checkpoints (gatekeepers) have shown great promise in preliminary clinical results, which may warrant further evaluations. In addition, inhibitors for other DNA repair pathways (caretakers) are also under active preclinical or clinical development. With these progresses and efforts, we envision that a new wave of innovations within DDR has come of age.
Topics: Humans; Cell Death; DNA Damage; Drug-Related Side Effects and Adverse Reactions; Genomic Instability
PubMed: 37679326
DOI: 10.1038/s41392-023-01548-8 -
Cell Research Mar 2022In response to DNA double-strand breaks (DSBs), DNA damage repair factors are recruited to DNA lesions and form nuclear foci. However, the underlying molecular mechanism...
In response to DNA double-strand breaks (DSBs), DNA damage repair factors are recruited to DNA lesions and form nuclear foci. However, the underlying molecular mechanism remains largely elusive. Here, by analyzing the localization of DSB repair factors in the XY body and DSB foci, we demonstrate that pre-ribosomal RNA (pre-rRNA) mediates the recruitment of DSB repair factors around DNA lesions. Pre-rRNA exists in the XY body, a DSB repair hub, during meiotic prophase, and colocalizes with DSB repair factors, such as MDC1, BRCA1 and TopBP1. Moreover, pre-rRNA-associated proteins and RNAs, such as ribosomal protein subunits, RNase MRP and snoRNAs, also localize in the XY body. Similar to those in the XY body, pre-rRNA and ribosomal proteins also localize at DSB foci and associate with DSB repair factors. RNA polymerase I inhibitor treatment that transiently suppresses transcription of rDNA but does not affect global protein translation abolishes foci formation of DSB repair factors as well as DSB repair. The FHA domain and PST repeats of MDC1 recognize pre-rRNA and mediate phase separation of DSB repair factors, which may be the molecular basis for the foci formation of DSB repair factors during DSB response.
Topics: Cell Cycle Proteins; DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Meiosis; Prophase; RNA Precursors; RNA, Ribosomal
PubMed: 34980897
DOI: 10.1038/s41422-021-00597-4 -
Neural Plasticity 2016
Topics: Animals; DNA Damage; Humans; Nerve Degeneration; Neuronal Plasticity
PubMed: 27313899
DOI: 10.1155/2016/1206840 -
International Journal of Molecular... Jun 2018
Topics: Animals; DNA Damage; DNA Repair; DNA Replication; Disease; Genome, Human; Humans; Phosphorylation
PubMed: 29958460
DOI: 10.3390/ijms19071902 -
International Journal of Molecular... Jun 2022The first aim of cell division is to pass the genetic material, intact and unchanged, to the next generation [...].
The first aim of cell division is to pass the genetic material, intact and unchanged, to the next generation [...].
Topics: Cell Division; DNA Damage; DNA Repair
PubMed: 35806207
DOI: 10.3390/ijms23137204 -
Frontiers in Immunology 2022
Topics: DNA Damage; DNA Repair; Immunity
PubMed: 36254318
DOI: 10.3389/fimmu.2022.1034689 -
International Journal of Molecular... Jan 2017
Topics: Animals; DNA Damage; DNA Repair; Diet; Disease; Epigenesis, Genetic; Humans; Oxidative Stress
PubMed: 28275213
DOI: 10.3390/ijms18010166 -
Biomolecules Dec 2022Developing B and T lymphocytes requires programmed DNA double-strand breaks followed by the activation of the DNA damage response (DDR) pathway and DNA repair [...].
Developing B and T lymphocytes requires programmed DNA double-strand breaks followed by the activation of the DNA damage response (DDR) pathway and DNA repair [...].
Topics: DNA Damage; DNA Repair; DNA Breaks, Double-Stranded; T-Lymphocytes
PubMed: 36671469
DOI: 10.3390/biom13010084 -
Trends in Cell Biology Feb 2020Mounting evidence suggests that DNA damage plays a central role in aging. Multiple tiers of defense have evolved to reduce the accumulation of DNA damage, including... (Review)
Review
Mounting evidence suggests that DNA damage plays a central role in aging. Multiple tiers of defense have evolved to reduce the accumulation of DNA damage, including reducing damaging molecules, repairing DNA damage, and inducing senescence or apoptosis in response to persistent DNA damage. Mutations in or failure of these pathways can lead to accelerated or premature aging and age-related decline in vital organs, supporting the hypothesis that maintaining a pristine genome is paramount for human health. Understanding how we cope with DNA damage could inform on the aging process and further on how deficient DNA maintenance manifests in age-related phenotypes. This knowledge may lead to the development of novel interventions promoting healthspan.
Topics: Aging; Animals; Cellular Senescence; DNA Damage; DNA Repair; Genome; Humans; Mutation
PubMed: 31917080
DOI: 10.1016/j.tcb.2019.12.001 -
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