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International Journal of Molecular... Jun 2023Chemically modified nucleic acid bases are sources of genomic instability and mutations but may also regulate gene expression as epigenetic or epitranscriptomic... (Review)
Review
Chemically modified nucleic acid bases are sources of genomic instability and mutations but may also regulate gene expression as epigenetic or epitranscriptomic modifications. Depending on the cellular context, they can have vastly diverse impacts on cells, from mutagenesis or cytotoxicity to changing cell fate by regulating chromatin organisation and gene expression. Identical chemical modifications exerting different functions pose a challenge for the cell's DNA repair machinery, as it needs to accurately distinguish between epigenetic marks and DNA damage to ensure proper repair and maintenance of (epi)genomic integrity. The specificity and selectivity of the recognition of these modified bases relies on DNA glycosylases, which acts as DNA damage, or more correctly, as modified bases sensors for the base excision repair (BER) pathway. Here, we will illustrate this duality by summarizing the role of uracil-DNA glycosylases, with particular attention to SMUG1, in the regulation of the epigenetic landscape as active regulators of gene expression and chromatin remodelling. We will also describe how epigenetic marks, with a special focus on 5-hydroxymethyluracil, can affect the damage susceptibility of nucleic acids and conversely how DNA damage can induce changes in the epigenetic landscape by altering the pattern of DNA methylation and chromatin structure.
Topics: DNA Repair; DNA Damage; Mutation; DNA Methylation
PubMed: 37373453
DOI: 10.3390/ijms241210307 -
Current Genetics Feb 2020DNA damage occurs abundantly during normal cellular proliferation. This necessitates that cellular DNA damage response and checkpoint pathways monitor the cellular DNA... (Review)
Review
DNA damage occurs abundantly during normal cellular proliferation. This necessitates that cellular DNA damage response and checkpoint pathways monitor the cellular DNA damage load and that DNA damage signaling is quantitative. Yet, how DNA lesions are counted and converted into a quantitative response remains poorly understood. We have recently obtained insights into this question investigating DNA damage signaling elicited by single-stranded DNA (ssDNA). Intriguingly, our findings suggest that local and global DNA damage signaling react differentially to increasing amounts of DNA damage. In this mini-review, we will discuss these findings and put them into perspective of current knowledge on the DNA damage response.
Topics: DNA Breaks, Double-Stranded; DNA Damage; Gene Expression Regulation; Genomic Instability; Humans; Protein Binding; Signal Transduction
PubMed: 31227863
DOI: 10.1007/s00294-019-01007-4 -
International Journal of Molecular... Aug 2023DNA double-strand breaks (DSBs) are a significant threat to cell viability due to the induction of genome instability and the potential loss of genetic information. One... (Review)
Review
DNA double-strand breaks (DSBs) are a significant threat to cell viability due to the induction of genome instability and the potential loss of genetic information. One of the key players for early DNA damage response is the conserved Mre11/Rad50 Nbs1/Xrs2 (MRN/X) complex, which is quickly recruited to the DNA's ruptured ends and is required for their tethering and their subsequent repair via different pathways. The MRN/X complex associates with several other proteins to exert its functions, but it also exploits sophisticated internal dynamic properties to orchestrate the several steps required to address the damage. In this review, we summarize the intrinsic molecular features of the MRN/X complex through biophysical, structural, and computational analyses in order to describe the conformational transitions that allow for this complex to accomplish its multiple functions.
Topics: DNA Breaks, Double-Stranded; Molecular Conformation; Cell Nucleus; Acid Anhydride Hydrolases; DNA; Cell Cycle Proteins; DNA Repair; DNA Repair Enzymes; DNA Damage
PubMed: 37569756
DOI: 10.3390/ijms241512377 -
International Journal of Molecular... Sep 2021Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx.... (Review)
Review
Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy‑refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the tumor suppressor, and overexpression of anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family. BCL2 homology 3 (BH3) mimetics represent a novel class of pro-apoptotic anti-cancer agents with a unique mode of action-direct targeting of mitochondria independently of gene aberrations. Consequently, BH3 mimetics can effectively eliminate even non-dividing malignant cells with adverse molecular cytogenetic alterations. Venetoclax, the nanomolar inhibitor of BCL2 anti-apoptotic protein has been approved for the therapy of CLL and AML. Numerous venetoclax-based combinatorial treatment regimens, next-generation BCL2 inhibitors, and myeloid cell leukemia 1 (MCL1) protein inhibitors, which are another class of BH3 mimetics with promising preclinical results, are currently being tested in several clinical trials in patients with diverse HM. These pivotal trials will soon answer critical questions and concerns about these innovative agents regarding not only their anti-tumor efficacy but also potential side effects, recommended dosages, and the optimal length of therapy as well as identification of reliable biomarkers of sensitivity or resistance. Effective harnessing of the full therapeutic potential of BH3 mimetics is a critical mission as it may directly translate into better management of the aggressive forms of HM and could lead to significantly improved survival parameters and quality of life in patients with urgent medical needs.
Topics: Animals; Apoptosis; Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; DNA Damage; Hematologic Neoplasms; Humans; Sulfonamides; Tumor Suppressor Protein p53
PubMed: 34576319
DOI: 10.3390/ijms221810157 -
Molecules (Basel, Switzerland) May 2020Epigenetic research has rapidly evolved into a dynamic field of genome biology. Chromatin regulation has been proved to be an essential aspect for all genomic processes,... (Review)
Review
Epigenetic research has rapidly evolved into a dynamic field of genome biology. Chromatin regulation has been proved to be an essential aspect for all genomic processes, including DNA repair. Chromatin structure is modified by enzymes and factors that deposit, erase, and interact with epigenetic marks such as DNA and histone modifications, as well as by complexes that remodel nucleosomes. In this review we discuss recent advances on how the chromatin state is modulated during this multi-step process of damage recognition, signaling, and repair. Moreover, we examine how chromatin is regulated when different pathways of DNA repair are utilized. Furthermore, we review additional modes of regulation of DNA repair, such as through the role of global and localized chromatin states in maintaining expression of DNA repair genes, as well as through the activity of epigenetic enzymes on non-nucleosome substrates. Finally, we discuss current and future applications of the mechanistic interplays between chromatin regulation and DNA repair in the context cancer treatment.
Topics: Chromatin Assembly and Disassembly; DNA Damage; DNA Repair; Epigenesis, Genetic; Humans
PubMed: 32471288
DOI: 10.3390/molecules25112496 -
Nucleic Acids Research Jan 2024DNA damage and its improper repair are the major source of genomic alterations responsible for many human diseases, particularly cancer. To aid researchers in...
DNA damage and its improper repair are the major source of genomic alterations responsible for many human diseases, particularly cancer. To aid researchers in understanding the underlying mechanisms of genome instability, a number of genome-wide profiling approaches have been developed to monitor DNA damage and repair events. The rapid accumulation of published datasets underscores the critical necessity of a comprehensive database to curate sequencing data on DNA damage and repair intermediates. Here, we present DNA Damage Atlas (DDA, http://www.bioinformaticspa.com/DDA/), the first large-scale repository of DNA damage and repair information. Currently, DDA comprises 6,030 samples from 262 datasets by 59 technologies, covering 16 species, 10 types of damage and 135 treatments. Data collected in DDA was processed through a standardized workflow, including quality checks, hotspots identification and a series of feature characterization for the hotspots. Notably, DDA encompasses analyses of highly repetitive regions, ribosomal DNA and telomere. DDA offers a user-friendly interface that facilitates browsing, searching, genome browser visualization, hotspots comparison and data downloading, enabling convenient and thorough exploration for datasets of interest. In summary, DDA will stand as a valuable resource for research in genome instability and its association with diseases.
Topics: Humans; Databases, Genetic; DNA Damage; Genomic Instability; Genomics
PubMed: 37831087
DOI: 10.1093/nar/gkad845 -
Trends in Biochemical Sciences Sep 2021Poly(ADP-ribosyl) polymerase-1 (PARP-1) is an abundant ADP-ribosyl transferase that regulates various biological processes. PARP-1 is widely recognized as a first-line... (Review)
Review
Poly(ADP-ribosyl) polymerase-1 (PARP-1) is an abundant ADP-ribosyl transferase that regulates various biological processes. PARP-1 is widely recognized as a first-line responder molecule in DNA damage response (DDR). Here, we review the full cycle of detecting DNA damage by PARP-1, PARP-1 activation upon DNA binding, and PARP-1 release from a DNA break. We also discuss the allosteric consequence upon binding of PARP inhibitors (PARPi) and the opportunity to tune its release from a DNA break. It is now possible to harness this new understanding to design novel PARPi for treating diseases where cell toxicity caused by PARP-1 'trapping' on DNA is either the desired consequence or entirely counterproductive.
Topics: Biological Phenomena; DNA Damage; Poly(ADP-ribose) Polymerase Inhibitors; Signal Transduction
PubMed: 33674152
DOI: 10.1016/j.tibs.2021.01.014 -
Frontiers in Endocrinology 2023
Topics: DNA Damage; DNA Repair; Endocrine System
PubMed: 36777343
DOI: 10.3389/fendo.2023.1138326 -
International Journal of Molecular... Jun 2023The average human cell suffers from approximately 10-10 DNA lesions per day [...].
The average human cell suffers from approximately 10-10 DNA lesions per day [...].
Topics: Humans; DNA; DNA Repair; DNA Damage
PubMed: 37298630
DOI: 10.3390/ijms24119682 -
Genes Jul 2021The nucleotide excision repair (NER) is essential for the repair of ultraviolet (UV)-induced DNA damage, such as cyclobutane pyrimidine dimers (CPDs) and... (Review)
Review
The nucleotide excision repair (NER) is essential for the repair of ultraviolet (UV)-induced DNA damage, such as cyclobutane pyrimidine dimers (CPDs) and 6,4-pyrimidine-pyrimidone dimers (6,4-PPs). Alterations in genes of the NER can lead to DNA damage repair disorders such as Xeroderma pigmentosum (XP). XP is a rare autosomal recessive genetic disorder associated with UV-sensitivity and early onset of skin cancer. Recently, extensive research has been conducted on the functional relevance of splice variants and their relation to cancer. Here, we focus on the functional relevance of alternative splice variants of XP genes.
Topics: DNA Damage; DNA Repair; Humans; Mutation; Pyrimidine Dimers; RNA Splicing; Xeroderma Pigmentosum
PubMed: 34440347
DOI: 10.3390/genes12081173