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Biomedicine & Pharmacotherapy =... Oct 2023Homologous recombination (HR) repair of DNA double-strand breaks (DSBs) is critical for maintaining genomic integrity and stability. Defects in HR increase the risk of... (Review)
Review
Homologous recombination (HR) repair of DNA double-strand breaks (DSBs) is critical for maintaining genomic integrity and stability. Defects in HR increase the risk of tumorigenesis. However, many human tumors exhibit enhanced HR repair capabilities, consequently endowing tumor cells with resistance to DNA-damaging chemotherapy and radiotherapy. This review summarizes the role of RNA methylation in HR repair and therapeutic resistance in human tumors. We also analyzed the interactions between RNA methylation and other HR-modulating modifications including histone acetylation, histone deacetylation, ubiquitination, deubiquitination, protein arginine methylation, and gene transcription. This review proposes that targeting RNA methylation is a promising approach to overcoming HR-mediated therapeutic resistance.
Topics: Humans; Recombinational DNA Repair; Methylation; Drug Resistance, Neoplasm; Histones; RNA
PubMed: 37659205
DOI: 10.1016/j.biopha.2023.115409 -
International Journal of Molecular... Oct 2023ADP-ribosylation is a post-translational modification of proteins that plays a key role in various cellular processes, including DNA repair. Recently, significant... (Review)
Review
ADP-ribosylation is a post-translational modification of proteins that plays a key role in various cellular processes, including DNA repair. Recently, significant progress has been made in understanding the mechanism and function of ADP-ribosylation in DNA repair. ADP-ribosylation can regulate the recruitment and activity of DNA repair proteins by facilitating protein-protein interactions and regulating protein conformations. Moreover, ADP-ribosylation can influence additional post-translational modifications (PTMs) of proteins involved in DNA repair, such as ubiquitination, methylation, acetylation, phosphorylation, and SUMOylation. The interaction between ADP-ribosylation and these additional PTMs can fine-tune the activity of DNA repair proteins and ensure the proper execution of the DNA repair process. In addition, PARP inhibitors have been developed as a promising cancer therapeutic strategy by exploiting the dependence of certain cancer types on the PARP-mediated DNA repair pathway. In this paper, we review the progress of ADP-ribosylation in DNA repair, discuss the crosstalk of ADP-ribosylation with additional PTMs in DNA repair, and summarize the progress of PARP inhibitors in cancer therapy.
Topics: Humans; Poly(ADP-ribose) Polymerases; Poly(ADP-ribose) Polymerase Inhibitors; ADP-Ribosylation; DNA Repair; Protein Processing, Post-Translational; Neoplasms; Proteins
PubMed: 37834477
DOI: 10.3390/ijms241915028 -
The EMBO Journal Sep 2023The conserved protein HMCES crosslinks to abasic (AP) sites in ssDNA to prevent strand scission and the formation of toxic dsDNA breaks during replication. Here, we...
The conserved protein HMCES crosslinks to abasic (AP) sites in ssDNA to prevent strand scission and the formation of toxic dsDNA breaks during replication. Here, we report a non-proteolytic release mechanism for HMCES-DNA-protein crosslinks (DPCs), which is regulated by DNA context. In ssDNA and at ssDNA-dsDNA junctions, HMCES-DPCs are stable, which efficiently protects AP sites against spontaneous incisions or cleavage by APE1 endonuclease. In contrast, HMCES-DPCs are released in dsDNA, allowing APE1 to initiate downstream repair. Mechanistically, we show that release is governed by two components. First, a conserved glutamate residue, within HMCES' active site, catalyses reversal of the crosslink. Second, affinity to the underlying DNA structure determines whether HMCES re-crosslinks or dissociates. Our study reveals that the protective role of HMCES-DPCs involves their controlled release upon bypass by replication forks, which restricts DPC formation to a necessary minimum.
Topics: DNA; Proteins; DNA Damage; DNA, Single-Stranded; DNA Repair
PubMed: 37519246
DOI: 10.15252/embj.2022113360 -
Bioscience Reports Feb 2024Seeds are the mode of propagation for most plant species and form the basis of both agriculture and ecosystems. Desiccation tolerant seeds, representative of most crop... (Review)
Review
Seeds are the mode of propagation for most plant species and form the basis of both agriculture and ecosystems. Desiccation tolerant seeds, representative of most crop species, can survive maturation drying to become metabolically quiescent. The desiccated state prolongs embryo viability and provides protection from adverse environmental conditions, including seasonal periods of drought and freezing often encountered in temperate regions. However, the capacity of the seed to germinate declines over time and culminates in the loss of seed viability. The relationship between environmental conditions (temperature and humidity) and the rate of seed deterioration (ageing) is well defined, but less is known about the biochemical and genetic factors that determine seed longevity. This review will highlight recent advances in our knowledge that provide insight into the cellular stresses and protective mechanisms that promote seed survival, with a focus on the roles of DNA repair and response mechanisms. Collectively, these pathways function to maintain the germination potential of seeds. Understanding the molecular basis of seed longevity provides important new genetic targets for the production of crops with enhanced resilience to changing climates and knowledge important for the preservation of plant germplasm in seedbanks.
Topics: Longevity; Ecosystem; DNA Repair; Temperature; Seeds; Germination
PubMed: 38324350
DOI: 10.1042/BSR20230809 -
Cell Death & Disease Nov 2023DNA double-strand breaks (DSBs) are the fatal type of DNA damage mostly induced by exposure genome to ionizing radiation or genotoxic chemicals. DSBs are mainly repaired... (Review)
Review
DNA double-strand breaks (DSBs) are the fatal type of DNA damage mostly induced by exposure genome to ionizing radiation or genotoxic chemicals. DSBs are mainly repaired by homologous recombination (HR) and nonhomologous end joining (NHEJ). To repair DSBs, a large amount of DNA repair factors was observed to be concentrated at the end of DSBs in a specific spatiotemporal manner to form a repair center. Recently, this repair center was characterized as a condensate derived from liquid-liquid phase separation (LLPS) of key DSBs repair factors. LLPS has been found to be the mechanism of membraneless organelles formation and plays key roles in a variety of biological processes. In this review, the recent advances and mechanisms of LLPS in the formation of DSBs repair-related condensates are summarized.
Topics: DNA Breaks, Double-Stranded; DNA Repair; DNA End-Joining Repair; DNA Damage; DNA
PubMed: 37968256
DOI: 10.1038/s41419-023-06267-0 -
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 -
Biochemical Society Transactions Feb 2024Meiotic recombination, a cornerstone of eukaryotic diversity and individual genetic identity, is essential for the creation of physical linkages between homologous... (Review)
Review
Meiotic recombination, a cornerstone of eukaryotic diversity and individual genetic identity, is essential for the creation of physical linkages between homologous chromosomes, facilitating their faithful segregation during meiosis I. This process requires that germ cells generate controlled DNA lesions within their own genome that are subsequently repaired in a specialised manner. Repair of these DNA breaks involves the modulation of existing homologous recombination repair pathways to generate crossovers between homologous chromosomes. Decades of genetic and cytological studies have identified a multitude of factors that are involved in meiotic recombination. Recent work has started to provide additional mechanistic insights into how these factors interact with one another, with DNA, and provide the molecular outcomes required for a successful meiosis. Here, we provide a review of the recent developments with a focus on protein structures and protein-protein interactions.
Topics: DNA Breaks, Double-Stranded; Homologous Recombination; DNA Repair; Meiosis; Chromosomes
PubMed: 38348856
DOI: 10.1042/BST20230712 -
Cell Reports Aug 2023The recombinase RAD51 plays a core role in DNA repair by homologous recombination (HR). The assembly and disassembly of RAD51 filament need to be orderly regulated by...
The recombinase RAD51 plays a core role in DNA repair by homologous recombination (HR). The assembly and disassembly of RAD51 filament need to be orderly regulated by mediators such as BRCA2 and anti-recombinases. To screen for potential regulators of RAD51, we perform RAD51 proximity proteomics and identify factor C1orf112. We further find that C1orf112 complexed with FIGNL1 facilitates RAD51 filament disassembly in the HR step of Fanconi anemia (FA) pathway. Specifically, C1orf112 physically interacts with FIGNL1 and enhances its protein stability. Meanwhile, the RAD51 filament disassembly activity of FIGNL1 is directly stimulated by C1orf112. BRCA2 directly interacts with C1orf112-FIGNL1 complex and functions upstream of this complex to protect RAD51 filament from premature disassembly. C1orf112- and FIGNL1-deficient cells are primarily sensitive to DNA interstrand cross-link (ICL) agents. Thus, these findings suggest an important function of C1orf112 in RAD51 regulation in the HR step of ICL repair by FA pathway.
Topics: Rad51 Recombinase; Proteins; BRCA2 Protein; DNA Repair; DNA; DNA Damage
PubMed: 37515771
DOI: 10.1016/j.celrep.2023.112907 -
Advanced Science (Weinheim,... Dec 2023Stromal antigen 2 (STAG2), a subunit of the cohesin complex, is recurrently mutated in various tumors. However, the role of STAG2 in DNA repair and its therapeutic...
Stromal antigen 2 (STAG2), a subunit of the cohesin complex, is recurrently mutated in various tumors. However, the role of STAG2 in DNA repair and its therapeutic implications are largely unknown. Here it is reported that knockout of STAG2 results in increased double-stranded breaks (DSBs) and chromosomal aberrations by reducing homologous recombination (HR) repair, and confers hypersensitivity to inhibitors of ataxia telangiectasia mutated (ATMi), Poly ADP Ribose Polymerase (PARPi), or the combination of both. Of note, the impaired HR by STAG2-deficiency is mainly attributed to the restored expression of KMT5A, which in turn methylates H4K20 (H4K20me0) to H4K20me1 and thereby decreases the recruitment of BRCA1-BARD1 to chromatin. Importantly, STAG2 expression correlates with poor prognosis of cancer patients. STAG2 is identified as an important regulator of HR and a potential therapeutic strategy for STAG2-mutant tumors is elucidated.
Topics: Humans; Recombinational DNA Repair; Cell Cycle Proteins; Poly(ADP-ribose) Polymerase Inhibitors; DNA Repair; Neoplasms; Cohesins; Ataxia Telangiectasia Mutated Proteins
PubMed: 37985839
DOI: 10.1002/advs.202302494 -
Trends in Biochemical Sciences Jan 2024DNA single-strand breaks (SSBs) are among the most common lesions arising in human cells, with tens to hundreds of thousands arising in each cell, each day. Cells have... (Review)
Review
DNA single-strand breaks (SSBs) are among the most common lesions arising in human cells, with tens to hundreds of thousands arising in each cell, each day. Cells have efficient mechanisms for the sensing and repair of these ubiquitous DNA lesions, but the failure of these processes to rapidly remove SSBs can lead to a variety of pathogenic outcomes. The threat posed by unrepaired SSBs is illustrated by the existence of at least six genetic diseases in which SSB repair (SSBR) is defective, all of which are characterised by neurodevelopmental and/or neurodegenerative pathology. Here, I review current understanding of how SSBs arise and impact on critical molecular processes, such as DNA replication and gene transcription, and their links to human disease.
Topics: Humans; DNA Repair; DNA Breaks, Single-Stranded; DNA Damage; DNA Replication; DNA
PubMed: 38040599
DOI: 10.1016/j.tibs.2023.11.001