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DNA Repair Aug 2023Cells have evolved an arsenal of molecular mechanisms to respond to continuous alterations in the primary structure of DNA. At the cellular level, DNA damage response... (Review)
Review
Cells have evolved an arsenal of molecular mechanisms to respond to continuous alterations in the primary structure of DNA. At the cellular level, DNA damage response proteins accumulate at sites of DNA damage and organize into nuclear foci. As recounted by Errol Friedberg, pioneering work on DNA repair in the 1930Â s was stimulated by collaborations between physicists and geneticists. In recent years, the introduction of ideas from physics on self-organizing compartments has taken the field of cell biology by storm. Percolation and phase separation theories are increasingly used to model the self-assembly of compartments, called biomolecular condensates, that selectively concentrate molecules without a surrounding membrane. In this review, we discuss these concepts in the context of the DNA damage response. We discuss how studies of DNA repair foci as condensates can link molecular mechanisms with cell physiological functions, provide new insights into regulatory mechanisms, and open new perspectives for targeting DNA damage responses for therapeutic purposes.
Topics: Proteins; Cell Nucleus; DNA Damage; DNA Repair
PubMed: 37320957
DOI: 10.1016/j.dnarep.2023.103524 -
Molecular Cell Jan 2024Completion of DNA replication relies on the ability of replication forks to traverse various types of DNA damage, actively transcribed regions, and structured DNA. The...
Completion of DNA replication relies on the ability of replication forks to traverse various types of DNA damage, actively transcribed regions, and structured DNA. The mechanisms enabling these processes are here referred to as DNA damage tolerance pathways. Here, we depict the stalled DNA replication fork structures with main DNA transactions and key factors contributing to the bypass of such blocks, replication restart, and completion. To view this SnapShot, open or download the PDF.
Topics: DNA Damage; DNA Damage Tolerance; DNA
PubMed: 38181760
DOI: 10.1016/j.molcel.2023.11.031 -
Advances in Cancer Research 2021The use of DNA-damaging agents such as radiotherapy and chemotherapy has been a mainstay treatment protocol for many cancers, including lung and prostate. Recently, FDA... (Review)
Review
The use of DNA-damaging agents such as radiotherapy and chemotherapy has been a mainstay treatment protocol for many cancers, including lung and prostate. Recently, FDA approval of inhibitors of DNA repair, and targeting innate immunity to enhance the efficacy of DNA-damaging agents have gained much attention. Yet, inherent or acquired resistance against DNA-damaging therapies persists as a fundamental drawback. While cancer eradication by causing cancer cell death through induction of apoptosis is the ultimate goal of anti-cancer treatments, autophagy and senescence are two major cellular responses induced by clinically tolerable doses of DNA-damaging therapies. Unlike apoptosis, autophagy and senescence can act as both pro-tumorigenic as well as tumor suppressive mechanisms. DNA damage-induced senescence is associated with a pro-inflammatory secretory phenotype, which contributes to reshaping the tumor- immune microenvironment. Moreover, PTEN (phosphatase and tensin homolog) is a tumor supressor deleted in many tumors, and has been implicated in both senescence and autophagy. This review presents an overview of the literature on the regulation and consequences of DNA damage- induced senescence in cancer cells, with a specific focus on autophagy and PTEN. Both autophagy and senescence occur concurrently in the same cells in response to DNA damaging agents. However, a deterministic relationship between these fundamental processes has been controversial. We present experimental evidence obtained with tumor cells, with a prime focus on two models of cancer, prostate and lung. A better understanding of mechanisms associated with DNA damage-induced cellular senescence is central to fully exploit the potential of DNA-damaging agents against cancer.
Topics: Animals; Apoptosis; Autophagy; Cellular Senescence; DNA Damage; Female; Humans; Male; PTEN Phosphohydrolase; Signal Transduction; Tumor Microenvironment
PubMed: 33858598
DOI: 10.1016/bs.acr.2021.01.006 -
Oral Oncology Sep 2020Ameloblastoma is a rare human disease of benign neoplasm odontogenic tumor with a lower prevalence but higher recurrence rate. Etiology of ameloblastoma is not fully... (Review)
Review
Ameloblastoma is a rare human disease of benign neoplasm odontogenic tumor with a lower prevalence but higher recurrence rate. Etiology of ameloblastoma is not fully understood thus lacks implementation of curative treatments. One of the proposed models of evolution of ameloblastoma is related to alteration in DNA damage and repair effects. Growing body of literature has associated defect in DNA damage and repair mechanisms with cancer risk and various adverse health outcomes in humans. Persistent defect of repair and escape of these genomic unstable cells from cell death mechanisms can contribute towards accumulation of oncogene driver or tumor suppressor mutations selective for malignant transformations. In addition, growth, progression and survival of tumor depends upon its DNA repair mechanisms too, thus identifying a DNA repair biomarker can be of advantageous to eliminate the tumor. Understanding the interconnection of oral lesion and role of various DNA repair mechanisms in context to ameloblastoma will assist to build up a platform for translational based research. This study is a literature review of research work published up to date in the field of ameloblastoma in regard to DNA damage and repair effects.
Topics: Ameloblastoma; DNA Damage; Humans
PubMed: 32474390
DOI: 10.1016/j.oraloncology.2020.104804 -
Chemical Research in Toxicology Jul 2023Aldehydes are widespread in the environment, with multiple sources such as food and beverages, industrial effluents, cigarette smoke, and additives. The toxic effects of... (Review)
Review
Aldehydes are widespread in the environment, with multiple sources such as food and beverages, industrial effluents, cigarette smoke, and additives. The toxic effects of exposure to several aldehydes have been observed in numerous studies. At the molecular level, aldehydes damage DNA, cross-link DNA and proteins, lead to lipid peroxidation, and are associated with increased disease risk including cancer. People genetically predisposed to aldehyde sensitivity exhibit severe health outcomes. In various diseases such as Fanconi's anemia and Cockayne syndrome, loss of aldehyde-metabolizing pathways in conjunction with defects in DNA repair leads to widespread DNA damage. Importantly, aldehyde-associated mutagenicity is being explored in a growing number of studies, which could offer key insights into how they potentially contribute to tumorigenesis. Here, we review the genotoxic effects of various aldehydes, focusing particularly on the DNA adducts underlying the mutagenicity of environmentally derived aldehydes. We summarize the chemical structures of the aldehydes and their predominant DNA adducts, discuss various methodologies, and , commonly used in measuring aldehyde-associated mutagenesis, and highlight some recent studies looking at aldehyde-associated mutation signatures and spectra. We conclude the Review with a discussion on the challenges and future perspectives of investigating aldehyde-associated mutagenesis.
Topics: Humans; Aldehydes; DNA Adducts; DNA Damage; DNA Repair; Mutagens; DNA
PubMed: 37363863
DOI: 10.1021/acs.chemrestox.3c00045 -
Seminars in Cancer Biology Oct 2022The acquisition of DNA damage is an early driving event in tumorigenesis. Premalignant lesions show activated DNA damage responses and inactivation of DNA damage... (Review)
Review
The acquisition of DNA damage is an early driving event in tumorigenesis. Premalignant lesions show activated DNA damage responses and inactivation of DNA damage checkpoints promotes malignant transformation. However, DNA damage is also a targetable vulnerability in cancer cells. This requires a detailed understanding of the cellular and molecular mechanisms governing DNA integrity. Here, we review current work on DNA damage in tumorigenesis. We discuss DNA double strand break repair, how repair pathways contribute to tumorigenesis, and how double strand breaks are linked to the tumor microenvironment. Next, we discuss the role of oncogenes in promoting DNA damage through replication stress. Finally, we discuss our current understanding on DNA damage in micronuclei and discuss therapies targeting these DNA damage pathways.
Topics: Humans; DNA Repair; DNA Damage; DNA Breaks, Double-Stranded; Cell Transformation, Neoplastic; DNA; Genomic Instability; Tumor Microenvironment
PubMed: 33905873
DOI: 10.1016/j.semcancer.2021.04.012 -
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 -
Genes Apr 2023Mutations of numerous genes involved in DNA replication, DNA repair, and DNA damage response (DDR) pathways lead to a variety of human diseases, including aging and...
Mutations of numerous genes involved in DNA replication, DNA repair, and DNA damage response (DDR) pathways lead to a variety of human diseases, including aging and cancer [...].
Topics: Humans; DNA Damage; DNA Repair; Mutation; Neoplasms; DNA Replication
PubMed: 37107651
DOI: 10.3390/genes14040893 -
The Enzymes 2022DNA is under a variety of assaults. As a result, different damages accumulate on DNA. These include base changes, single-strand breaks and double-strand breaks. In this...
DNA is under a variety of assaults. As a result, different damages accumulate on DNA. These include base changes, single-strand breaks and double-strand breaks. In this volume and also briefly in the following volume, we discuss DNA damage and double-strand breaks. In particular, we focus on double-strand breaks. We discuss types of double-strand breaks as well as methods to detect them. We also discuss how DNA breaks are formed.
Topics: DNA Damage; DNA Repair; DNA
PubMed: 36336403
DOI: 10.1016/bs.enz.2022.08.001 -
Neurobiology of Disease Jan 2021Traumatic brain injury (TBI) is known to promote significant DNA damage irrespective of age, sex, and species. Chemical as well as structural DNA modification start... (Review)
Review
Traumatic brain injury (TBI) is known to promote significant DNA damage irrespective of age, sex, and species. Chemical as well as structural DNA modification start within minutes and persist for days after TBI. Although several DNA repair pathways are induced following TBI, the simultaneous downregulation of some of the genes and proteins of these pathways leads to an aberrant overall DNA repair process. In many instances, DNA damages escape even the most robust repair mechanisms, especially when the repair process becomes overwhelmed or becomes inefficient by severe or repeated injuries. The persisting DNA damage and/or lack of DNA repair contributes to long-term functional deficits. In this review, we discuss the mechanisms of TBI-induced DNA damage and repair. We further discussed the putative experimental therapies that target the members of the DNA repair process for improved outcome following TBI.
Topics: Animals; Brain Injuries, Traumatic; DNA Damage; DNA Repair; Humans
PubMed: 33127471
DOI: 10.1016/j.nbd.2020.105143