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ACS Chemical Biology Oct 2017In 2011, Varela et al. reported that the PBRM1 gene is mutated in approximately 40% of clear cell renal cell carcinoma cases. Since then, the number of studies relating... (Review)
Review
In 2011, Varela et al. reported that the PBRM1 gene is mutated in approximately 40% of clear cell renal cell carcinoma cases. Since then, the number of studies relating PBRM1 mutations to cancers has substantially increased. BAF180 has now been linked to more than 30 types of cancers, including ccRCC, cholangiocarcinomas, esophageal squamous cell carcinoma, bladder cancer, and breast cancer. The mutations associated with BAF180 are most often truncations, which result in a loss of protein expression. This loss has been shown to adversely affect the expression of genes, likely because BAF180 is the chromatin recognition subunit of PBAF. In addition, BAF180 functions in numerous DNA repair mechanisms. Its roles in mediating DNA repair are likely the mechanism by which BAF180 acts a tumor suppressor protein. As research on this protein gains more interest, scientists will begin to piece together the complicated puzzle of the BAF180 protein and why its loss often results in cancer.
Topics: DNA Repair; DNA-Binding Proteins; Gene Expression Regulation; Humans; Mutation; Neoplasms; Nuclear Proteins; Transcription Factors
PubMed: 28921948
DOI: 10.1021/acschembio.7b00541 -
Genes Oct 2022In response to DNA double strand breaks (DSB), repair proteins accumulate at damaged sites, forming membrane-less condensates or "foci". The formation of these foci and... (Review)
Review
In response to DNA double strand breaks (DSB), repair proteins accumulate at damaged sites, forming membrane-less condensates or "foci". The formation of these foci and their disassembly within the proper time window are essential for genome integrity. However, how these membrane-less sub-compartments are formed, maintained and disassembled remains unclear. Recently, several studies across different model organisms proposed that DNA repair foci form via liquid phase separation. In this review, we discuss the current research investigating the physical nature of repair foci. First, we present the different models of condensates proposed in the literature, highlighting the criteria to differentiate them. Second, we discuss evidence of liquid phase separation at DNA repair sites and the limitations of this model to fully describe structures formed in response to DNA damage. Finally, we discuss the origin and possible function of liquid phase separation for DNA repair processes.
Topics: DNA-Binding Proteins; DNA Breaks, Double-Stranded; DNA Repair; DNA Damage; DNA
PubMed: 36292731
DOI: 10.3390/genes13101846 -
Advances in Experimental Medicine and... 2017Radiotherapy acts as an important component of breast cancer management, which significantly decreases local recurrence in patients treated with conservative surgery or... (Review)
Review
Radiotherapy acts as an important component of breast cancer management, which significantly decreases local recurrence in patients treated with conservative surgery or with radical mastectomy. On the foundation of technological innovation of radiotherapy setting, precision radiotherapy of cancer has been widely applied in recent years. DNA damage and its repair mechanism are the vital factors which lead to the formation of tumor. Moreover, the status of DNA damage repair in cancer cells has been shown to influence patient response to the therapy, including radiotherapy. Some genes can affect the radiosensitivity of tumor cell by regulating the DNA damage repair pathway. This chapter will describe the potential application of DNA damage repair in precision radiotherapy of breast cancer.
Topics: Breast Neoplasms; Combined Modality Therapy; DNA Damage; DNA Repair; Female; Humans; Neoplasm Recurrence, Local; Radiation Tolerance
PubMed: 29282681
DOI: 10.1007/978-981-10-6020-5_5 -
DNA Repair Jul 2021Genome integrity is constantly challenged by various DNA lesions with DNA double-strand breaks (DSBs) as the most cytotoxic lesions. In order to faithfully repair DSBs,...
Genome integrity is constantly challenged by various DNA lesions with DNA double-strand breaks (DSBs) as the most cytotoxic lesions. In order to faithfully repair DSBs, DNA damage response (DDR) signaling networks have evolved, which organize many multi-protein complexes to deal with the encountered DNA damage. Spatiotemporal dynamics of these protein complexes at DSBs are mainly modulated by post-translational modifications (PTMs). One of the most well-studied PTMs in DDR is ubiquitylation which can orchestrate cellular responses to DSBs, promote accurate DNA repair, and maintain genome integrity. Here, we summarize the recent advances of ubiquitin-dependent signaling in DDR and discuss how ubiquitylation crosstalks with other PTMs to control fundamental biological processes in DSB repair.
Topics: DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; Humans; Recombinational DNA Repair; Signal Transduction; Ubiquitination
PubMed: 33990032
DOI: 10.1016/j.dnarep.2021.103129 -
Genes Mar 2022Pericentromeric heterochromatin is mostly composed of repetitive DNA sequences prone to aberrant recombination. Cells have developed highly specialized mechanisms to... (Review)
Review
Pericentromeric heterochromatin is mostly composed of repetitive DNA sequences prone to aberrant recombination. Cells have developed highly specialized mechanisms to enable 'safe' homologous recombination (HR) repair while preventing aberrant recombination in this domain. Understanding heterochromatin repair responses is essential to understanding the critical mechanisms responsible for genome integrity and tumor suppression. Here, we review the tools, approaches, and methods currently available to investigate double-strand break (DSB) repair in pericentromeric regions, and also suggest how technologies recently developed for euchromatin repair studies can be adapted to characterize responses in heterochromatin. With this ever-growing toolkit, we are witnessing exciting progress in our understanding of how the 'dark matter' of the genome is repaired, greatly improving our understanding of genome stability mechanisms.
Topics: DNA Breaks, Double-Stranded; DNA Repair; Euchromatin; Heterochromatin; Recombinational DNA Repair
PubMed: 35328082
DOI: 10.3390/genes13030529 -
Life Sciences Apr 2022Various DNA breaks created via programmable CRISPR/Cas9 nuclease activity results in different intracellular DNA break repair pathways. Based on the cellular repair... (Review)
Review
Various DNA breaks created via programmable CRISPR/Cas9 nuclease activity results in different intracellular DNA break repair pathways. Based on the cellular repair pathways, CRISPR-based gene knock-in methods can be categorized into two major strategies: 1) Homology-independent strategies which are targeted insertion events based on non-homologous end joining, and 2) Homology-dependent strategies which are targeted insertion events based on the homology-directed repair. This review elaborates on various gene knock-in methods in mammalian cells using the CRISPR/Cas9 system and in sync with DNA-break repair pathways. Gene knock-in methods are applied in functional genomics and gene therapy. To compensate or correct genetic defects, different CRISPR-based gene knock-in strategies can be used. Thus, researchers need to make a conscious decision about the most suitable knock-in method. For a successful gene-targeted insertion, some determinant factors should be considered like cell cycle, dominant DNA repair pathway, size of insertions, and donor properties. In this review, different aspects of each gene knock-in strategy are discussed to provide a framework for choosing the most appropriate gene knock-in method in different applications.
Topics: Animals; CRISPR-Cas Systems; DNA; DNA Breaks; DNA End-Joining Repair; DNA Repair; Gene Editing; Gene Knock-In Techniques; Humans; Recombinational DNA Repair
PubMed: 35182556
DOI: 10.1016/j.lfs.2022.120409 -
Current Opinion in Cell Biology Jun 2018DNA is labile and constantly subject to damage. In addition to external mutagens, DNA is continuously damaged by the aqueous environment, cellular metabolites and is... (Review)
Review
DNA is labile and constantly subject to damage. In addition to external mutagens, DNA is continuously damaged by the aqueous environment, cellular metabolites and is prone to strand breakage during replication. Cell duplication is orchestrated by the cell division cycle and specific DNA structures are processed differently depending on where in the cell cycle they are detected. This is often because a specific structure is physiological in one context, for example during DNA replication, while indicating a potentially pathological event in another, such as interphase or mitosis. Thus, contextualising the biochemical entity with respect to cell cycle progression provides information necessary to appropriately regulate DNA processing activities. We review the links between DNA repair and cell cycle context, drawing together recent advances.
Topics: Cell Cycle; DNA Damage; DNA Repair; Humans
PubMed: 29587168
DOI: 10.1016/j.ceb.2018.03.006 -
Essays in Biochemistry Jul 2017DNA is the carrier of genetic information and the primary template from which all cellular information is ultimately derived. Changes in the DNA information content... (Review)
Review
DNA is the carrier of genetic information and the primary template from which all cellular information is ultimately derived. Changes in the DNA information content through mutation generate diversity for evolution through natural selection but are also a source of deleterious effects. It has since long been hypothesized that mutation accumulation in somatic cells of multicellular organisms could causally contribute to age-related cellular degeneration and death. Assays to detect different types of mutations, from base substitutions to large chromosomal aberrations, have been developed and show unequivocally that mutations accumulate in different tissues and cell types of ageing humans and animals. More recently, next-generation sequencing-based methods have been developed to accurately determine the complete landscape of base substitution mutations in single cells. The first results show that the somatic mutation rate is much higher than the germline mutation rate and that base substitution loads in somatic cells are high enough to potentially affect cellular function.
Topics: Aging; Animals; DNA Repair; Genomic Instability; Humans; Mutation
PubMed: 28550046
DOI: 10.1042/EBC20160082 -
Briefings in Functional Genomics Mar 2021Post-translational modifications of proteins are well-established participants in DNA damage response (DDR) pathways, which function in the maintenance of genome... (Review)
Review
Post-translational modifications of proteins are well-established participants in DNA damage response (DDR) pathways, which function in the maintenance of genome integrity. Emerging evidence is starting to reveal the involvement of modifications on RNA in the DDR. RNA modifications are known regulators of gene expression but how and if they participate in DNA repair and genome maintenance has been poorly understood. Here, we review several studies that have now established RNA modifications as key components of DNA damage responses. RNA modifying enzymes and the binding proteins that recognize these modifications localize to and participate in the repair of UV-induced and DNA double-strand break lesions. RNA modifications have a profound effect on DNA-RNA hybrids (R-loops) at DNA damage sites, a structure known to be involved in DNA repair and genome stability. Given the importance of the DDR in suppressing mutations and human diseases such as neurodegeneration, immunodeficiencies, cancer and aging, RNA modification pathways may be involved in human diseases not solely through their roles in gene expression but also by their ability to impact DNA repair and genome stability.
Topics: DNA Damage; DNA Repair; Genome; Genomic Instability; Humans; RNA
PubMed: 33279952
DOI: 10.1093/bfgp/elaa022 -
Cells Apr 2021Miroslav Radman's far-sighted ideas have penetrated many aspects of our study of the repair of broken eukaryotic chromosomes. For over 35 years my lab has studied... (Review)
Review
Miroslav Radman's far-sighted ideas have penetrated many aspects of our study of the repair of broken eukaryotic chromosomes. For over 35 years my lab has studied different aspects of the repair of chromosomal breaks in the budding yeast, . From the start, we have made what we thought were novel observations that turned out to have been predicted by Miro's extraordinary work in the bacterium and then later in the radiation-resistant . In some cases, we have been able to extend some of his ideas a bit further.
Topics: DNA Damage; DNA Repair; DNA Replication; Recombination, Genetic; SOS Response, Genetics; Saccharomyces cerevisiae
PubMed: 33923882
DOI: 10.3390/cells10040945