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Nature Communications Mar 2018Genetic studies in yeast indicate that RNA transcripts facilitate homology-directed DNA repair in a manner that is dependent on RAD52. The molecular basis for so-called...
Genetic studies in yeast indicate that RNA transcripts facilitate homology-directed DNA repair in a manner that is dependent on RAD52. The molecular basis for so-called RNA-DNA repair, however, remains unknown. Using reconstitution assays, we demonstrate that RAD52 directly cooperates with RNA as a sequence-directed ribonucleoprotein complex to promote two related modes of RNA-DNA repair. In a RNA-bridging mechanism, RAD52 assembles recombinant RNA-DNA hybrids that coordinate synapsis and ligation of homologous DNA breaks. In an RNA-templated mechanism, RAD52-mediated RNA-DNA hybrids enable reverse transcription-dependent RNA-to-DNA sequence transfer at DNA breaks that licenses subsequent DNA recombination. Notably, we show that both mechanisms of RNA-DNA repair are promoted by transcription of a homologous DNA template in trans. In summary, these data elucidate how RNA transcripts cooperate with RAD52 to coordinate homology-directed DNA recombination and repair in the absence of a DNA donor, and demonstrate a direct role for transcription in RNA-DNA repair.
Topics: DNA Breaks, Double-Stranded; DNA Repair; RNA; Rad52 DNA Repair and Recombination Protein; Recombinational DNA Repair; Saccharomyces cerevisiae Proteins
PubMed: 29545568
DOI: 10.1038/s41467-018-03483-7 -
International Journal of Molecular... Jun 2018
Topics: Animals; DNA Damage; DNA Repair; Humans; Mutagenesis; Neoplasms
PubMed: 29899224
DOI: 10.3390/ijms19061767 -
International Journal of Biological... 2023Liquid‒liquid phase separation (LLPS) is a phenomenon driven by weak interactions between biomolecules, such as proteins and nucleic acids, that leads to the formation... (Review)
Review
Liquid‒liquid phase separation (LLPS) is a phenomenon driven by weak interactions between biomolecules, such as proteins and nucleic acids, that leads to the formation of distinct liquid-like condensates. Through LLPS, membraneless condensates are formed, selectively concentrating specific proteins while excluding other molecules to maintain normal cellular functions. Emerging evidence shows that cancer-related mutations cause aberrant condensate assembly, resulting in disrupted signal transduction, impaired DNA repair, and abnormal chromatin organization and eventually contributing to tumorigenesis. The objective of this review is to summarize recent advancements in understanding the potential implications of LLPS in the contexts of cancer progression and therapeutic interventions. By interfering with LLPS, it may be possible to restore normal cellular processes and inhibit tumor progression. The underlying mechanisms and potential drug targets associated with LLPS in cancer are discussed, shedding light on promising opportunities for novel therapeutic interventions.
Topics: Humans; Carcinogenesis; Cell Transformation, Neoplastic; DNA Repair; Drug Delivery Systems; Mutation
PubMed: 37705755
DOI: 10.7150/ijbs.81521 -
Molekuliarnaia Biologiia 2021The base and nucleotide excision DNA repair (BER and NER) systems are aimed at removing specific types of damaged DNA, i.e., oxidized, alkylated, or deaminated bases in... (Review)
Review
The base and nucleotide excision DNA repair (BER and NER) systems are aimed at removing specific types of damaged DNA, i.e., oxidized, alkylated, or deaminated bases in the case of BER and bulky damage caused by UV radiation or chemical carcinogens in the case of NER. In some cases, however, the repair process follows a more complex scenario, which implies that the repair pathways exchange proteins and interact with each other to form a common interactome. This review describes the BER and NER mechanisms and discusses the current data on the involvement of the NER proteins in the repair of DNA lesions caused by oxidative stress and the BER proteins in the removal of bulky DNA adducts. We also discuss the role of poly(ADP-ribose) polymerase 1 in the regulation of the BER and NER processes and their coordination in the repair of complex (cluster) lesions.
Topics: DNA; DNA Damage; DNA Repair; Nucleotides; Oxidative Stress
PubMed: 33871434
DOI: 10.31857/S0026898421020129 -
Genes Jun 2023Cells are constantly assaulted by endogenous and exogenous sources of DNA damage that threaten genome stability [...].
Cells are constantly assaulted by endogenous and exogenous sources of DNA damage that threaten genome stability [...].
Topics: Humans; DNA Repair; DNA Damage; Genomic Instability
PubMed: 37510290
DOI: 10.3390/genes14071385 -
Cold Spring Harbor Perspectives in... Jun 2013Alternative excision repair (AER) is a category of excision repair initiated by a single nick, made by an endonuclease, near the site of DNA damage, and followed by... (Review)
Review
Alternative excision repair (AER) is a category of excision repair initiated by a single nick, made by an endonuclease, near the site of DNA damage, and followed by excision of the damaged DNA, repair synthesis, and ligation. The ultraviolet (UV) damage endonuclease in fungi and bacteria introduces a nick immediately 5' to various types of UV damage and initiates its excision repair that is independent of nucleotide excision repair (NER). Endo IV-type apurinic/apyrimidinic (AP) endonucleases from Escherichia coli and yeast and human Exo III-type AP endonuclease APEX1 introduce a nick directly and immediately 5' to various types of oxidative base damage besides the AP site, initiating excision repair. Another endonuclease, endonuclease V from bacteria to humans, binds deaminated bases and cleaves the phosphodiester bond located 1 nucleotide 3' of the base, leading to excision repair. A single-strand break in DNA is one of the most frequent types of DNA damage within cells and is repaired efficiently. AER makes use of such repair capability of single-strand breaks, removes DNA damage, and has an important role in complementing BER and NER.
Topics: Animals; DNA Breaks, Single-Stranded; DNA Damage; DNA Repair; DNA Repair Enzymes; Endonucleases; Humans; Models, Biological; Species Specificity; Yeasts
PubMed: 23645854
DOI: 10.1101/cshperspect.a012617 -
International Journal of Molecular... Dec 2012The alteration of tumorigenic pathways leading to cancer is a degenerative disease process typically involving inactivation of tumor suppressor proteins and... (Review)
Review
The alteration of tumorigenic pathways leading to cancer is a degenerative disease process typically involving inactivation of tumor suppressor proteins and hyperactivation of oncogenes. One such oncogenic protein product is the murine double-minute 2, or Mdm2. While, Mdm2 has been primarily associated as the negative regulator of the p53 tumor suppressor protein there are many p53-independent roles demonstrated for this oncogene. DNA damage and chemotherapeutic agents are known to activate Mdm2 and DNA repair pathways. There are five primary DNA repair pathways involved in the maintenance of genomic integrity: Nucleotide excision repair (NER), Base excision repair (BER), Mismatch repair (MMR), Non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we will briefly describe these pathways and also delineate the functional interaction of Mdm2 with multiple DNA repair proteins. We will illustrate the importance of these interactions with Mdm2 and discuss how this is important for tumor progression, cellular proliferation in cancer.
Topics: Animals; Carcinogenesis; DNA Damage; DNA Mismatch Repair; DNA Repair; Homologous Recombination; Humans; Proto-Oncogene Proteins c-mdm2; Signal Transduction
PubMed: 23208375
DOI: 10.3390/ijms131216373 -
International Journal of Molecular... Mar 2022The repair of DNA damage is a crucial process for the correct maintenance of genetic information, thus, allowing the proper functioning of cells. Among the different... (Review)
Review
The repair of DNA damage is a crucial process for the correct maintenance of genetic information, thus, allowing the proper functioning of cells. Among the different types of lesions occurring in DNA, double-strand breaks (DSBs) are considered the most harmful type of lesion, which can result in significant loss of genetic information, leading to diseases, such as cancer. DSB repair occurs through two main mechanisms, called non-homologous end joining (NHEJ) and homologous recombination repair (HRR). There is evidence showing that miRNAs play an important role in the regulation of genes acting in NHEJ and HRR mechanisms, either through direct complementary binding to mRNA targets, thus, repressing translation, or by targeting other genes involved in the transcription and activity of DSB repair genes. Therefore, alteration of miRNA expression has an impact on the ability of cells to repair DSBs, which, in turn, affects cancer therapy sensitivity. This latter gives account of the importance of miRNAs as regulators of NHEJ and HRR and places them as a promising target to improve cancer therapy. Here, we review recent reports demonstrating an association between miRNAs and genes involved in NHEJ and HRR. We employed the Web of Science search query TS ("gene official symbol/gene aliases*" AND "miRNA/microRNA/miR-") and focused on articles published in the last decade, between 2010 and 2021. We also performed a data analysis to represent miRNA-mRNA validated interactions from TarBase v.8, in order to offer an updated overview about the role of miRNAs as regulators of DSB repair.
Topics: DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; MicroRNAs; RNA, Messenger; Recombinational DNA Repair
PubMed: 35328651
DOI: 10.3390/ijms23063231 -
International Journal of Biological... 2017One of the DNA repair machineries is activated by Poly (ADP-ribose) Polymerase (PARP) enzyme. Particularly, this enzyme is involved in repair of damages to single-strand... (Review)
Review
One of the DNA repair machineries is activated by Poly (ADP-ribose) Polymerase (PARP) enzyme. Particularly, this enzyme is involved in repair of damages to single-strand DNA, thus decreasing the chances of generating double-strand breaks in the genome. Therefore, the concept to block PARP enzymes by PARP inhibitor (PARPi) was appreciated in cancer treatment. PARPi has been designed and tested for many years and became a potential supplement for the conventional chemotherapy. However, increasing evidence indicates the appearance of the resistance to this treatment. Specifically, cancer cells may acquire new mutations or events that overcome the positive effect of these drugs. This paper describes several molecular mechanisms of PARPi resistance which were reported most recently, and summarizes some strategies to reverse this type of drug resistance.
Topics: Animals; BRCA1 Protein; DNA Repair; Drug Resistance, Neoplasm; Humans; MicroRNAs; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 28255272
DOI: 10.7150/ijbs.17240 -
STAR Protocols Mar 2022The repair products of double-stranded DNA breaks (DSBs) are crucial for investigating the mechanism underlying DNA damage repair as well as evaluating the safety and...
The repair products of double-stranded DNA breaks (DSBs) are crucial for investigating the mechanism underlying DNA damage repair as well as evaluating the safety and efficiency of gene-editing; however, a comprehensively quantitative assay remains to be established. Here, we describe the step-by-step instructions of the primer extension-mediated sequencing (PEM-seq), followed by the framework of data processing and statistical analysis. PEM-seq presents a full spectrum of repair outcomes for both genome-editing-induced and endogenous DSBs in mouse and human cells. For complete details on the use and execution of this profile, please refer to Gan et al. (2021), Yin et al. (2019), Liu et al. (2021a), and Zhang et al. (2021).
Topics: Animals; DNA Breaks, Double-Stranded; DNA Repair; Gene Editing; Mice
PubMed: 35462794
DOI: 10.1016/j.xpro.2021.101088