scholarly journals Histone Modifications and the Maintenance of Telomere Integrity

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 199 ◽  
Author(s):  
Meagan Jezek ◽  
Erin Green
Keyword(s):  
Histone Modifications ◽  
Current Knowledge ◽  
Telomere Maintenance ◽  
Model Systems ◽  
Future Research ◽  
Dna Double Strand Breaks ◽  
Post Translational Modifications ◽  
Strand Breaks ◽  
Integral Role ◽  
Protective Proteins

Telomeres, the nucleoprotein structures at the ends of eukaryotic chromosomes, play an integral role in protecting linear DNA from degradation. Dysregulation of telomeres can result in genomic instability and has been implicated in increased rates of cellular senescence and many diseases, including cancer. The integrity of telomeres is maintained by a coordinated network of proteins and RNAs, such as the telomerase holoenzyme and protective proteins that prevent the recognition of the telomere ends as a DNA double-strand breaks. The structure of chromatin at telomeres and within adjacent subtelomeres has been implicated in telomere maintenance pathways in model systems and humans. Specific post-translational modifications of histones, including methylation, acetylation, and ubiquitination, have been shown to be necessary for maintaining a chromatin environment that promotes telomere integrity. Here we review the current knowledge regarding the role of histone modifications in maintaining telomeric and subtelomeric chromatin, discuss the implications of histone modification marks as they relate to human disease, and highlight key areas for future research.

scholarly journals Post-Translational Modification of MRE11: Its Implication in DDR and Diseases

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1158
Author(s):  
Ruiqing Lu ◽  
Han Zhang ◽  
Yinan Jiang ◽  
Zhaoqi Wang ◽  
Litao Sun ◽  
...  
Keyword(s):  
Meiotic Recombination ◽  
Genomic Stability ◽  
Double Strand Breaks ◽  
Telomere Maintenance ◽  
Dna Double Strand Breaks ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Strand Breaks ◽  
Cellular Processes ◽  
Dna Ends

Maintaining genomic stability is vital for cells as well as individual organisms. The meiotic recombination-related gene MRE11 (meiotic recombination 11) is essential for preserving genomic stability through its important roles in the resection of broken DNA ends, DNA damage response (DDR), DNA double-strand breaks (DSBs) repair, and telomere maintenance. The post-translational modifications (PTMs), such as phosphorylation, ubiquitination, and methylation, regulate directly the function of MRE11 and endow MRE11 with capabilities to respond to cellular processes in promptly, precisely, and with more diversified manners. Here in this paper, we focus primarily on the PTMs of MRE11 and their roles in DNA response and repair, maintenance of genomic stability, as well as their association with diseases such as cancer.

scholarly journals The role of ubiquitin-dependent segregase p97 (VCP or Cdc48) in chromatin dynamics after DNA double strand breaks

2017 ◽  
Vol 372 (1731) ◽  
pp. 20160282 ◽  
Author(s):  
Ignacio Torrecilla ◽  
Judith Oehler ◽  
Kristijan Ramadan
Keyword(s):  
Dna Repair ◽  
Current Knowledge ◽  
Dna Lesions ◽  
Chromatin Remodelling ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Chromatin Dynamics ◽  
Strand Breaks ◽  
Signalling Molecules

DNA double strand breaks (DSBs) are the most cytotoxic DNA lesions and, if not repaired, lead to chromosomal rearrangement, genomic instability and cell death. Cells have evolved a complex network of DNA repair and signalling molecules which promptly detect and repair DSBs, commonly known as the DNA damage response (DDR). The DDR is orchestrated by various post-translational modifications such as phosphorylation, methylation, ubiquitination or SUMOylation. As DSBs are located in complex chromatin structures, the repair of DSBs is engineered at two levels: (i) at sites of broken DNA and (ii) at chromatin structures that surround DNA lesions. Thus, DNA repair and chromatin remodelling machineries must work together to efficiently repair DSBs. Here, we summarize the current knowledge of the ubiquitin-dependent molecular unfoldase/segregase p97 (VCP in vertebrates and Cdc48 in worms and lower eukaryotes) in DSB repair. We identify p97 as an essential factor that regulates DSB repair. p97-dependent extraction of ubiquitinated substrates mediates spatio-temporal protein turnover at and around the sites of DSBs, thus orchestrating chromatin remodelling and DSB repair. As p97 is a druggable target, p97 inhibition in the context of DDR has great potential for cancer therapy, as shown for other DDR components such as PARP, ATR and CHK1. This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.

scholarly journals Ku and the Stability of the Genome

2002 ◽  
Vol 2 (2) ◽  
pp. 61-65 ◽  
Author(s):  
Anna A. Friedl
Keyword(s):  
Double Strand Breaks ◽  
Telomere Maintenance ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Cellular Processes ◽  
Molecular Functions ◽  
Ku Proteins ◽  
The Stability ◽  
Dependent Processes

Ku proteins are associated with a variety of cellular processes such as repair of DNA-double-strand breaks, telomere maintenance and retrotransposition. In recent years, we have learned a lot about their cellular and molecular functions and it has turned out that Ku-dependent processes affect the stability of the genome, both positively and negatively, in several ways. This article gives an overview on the role of Ku in determining the shape of the genome.

scholarly journals Mdt1 Facilitates Efficient Repair of Blocked DNA Double-Strand Breaks and Recombinational Maintenance of Telomeres

2007 ◽  
Vol 27 (18) ◽  
pp. 6532-6545 ◽  
Author(s):  
Brietta L. Pike ◽  
Jörg Heierhorst
Keyword(s):  
Dna Recombination ◽  
Double Strand Breaks ◽  
Telomere Maintenance ◽  
Type I ◽  
Dna Double Strand Breaks ◽  
Drug Induced ◽  
Exogenous Dna ◽  
Strand Breaks ◽  
Dramatic Shift ◽  
Recombination Pathway

ABSTRACT DNA recombination plays critical roles in DNA repair and alternative telomere maintenance. Here we show that absence of the SQ/TQ cluster domain-containing protein Mdt1 (Ybl051c) renders Saccharomyces cerevisiae particularly hypersensitive to bleomycin, a drug that causes 3′-phospho-glycolate-blocked DNA double-strand breaks (DSBs). mdt1Δ also hypersensitizes partially recombination-defective cells to camptothecin-induced 3′-phospho-tyrosyl protein-blocked DSBs. Remarkably, whereas mdt1Δ cells are unable to restore broken chromosomes after bleomycin treatment, they efficiently repair “clean” endonuclease-generated DSBs. Epistasis analyses indicate that MDT1 acts in the repair of bleomycin-induced DSBs by regulating the efficiency of the homologous recombination pathway as well as telomere-related functions of the KU complex. Moreover, mdt1Δ leads to severe synthetic growth defects with a deletion of the recombination facilitator and telomere-positioning factor gene CTF18 already in the absence of exogenous DNA damage. Importantly, mdt1Δ causes a dramatic shift from the usually prevalent type II to the less-efficient type I pathway of recombinational telomere maintenance in the absence of telomerase in liquid senescence assays. As telomeres resemble protein-blocked DSBs, the results indicate that Mdt1 acts in a novel blocked-end-specific recombination pathway that is required for the efficiency of both drug-induced DSB repair and telomerase-independent telomere maintenance.

scholarly journals Beyond reversal: ubiquitin and ubiquitin-like proteases and the orchestration of the DNA double strand break repair response

2019 ◽  
Vol 47 (6) ◽  
pp. 1881-1893
Author(s):  
Alexander J. Garvin
Keyword(s):  
Protein Interactions ◽  
Cellular Response ◽  
Strand Break ◽  
Central Component ◽  
Protein Protein Interactions ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Post Translational Modifications ◽  
Strand Breaks ◽  
Dna Double Strand Break

The cellular response to genotoxic DNA double strand breaks (DSBs) uses a multitude of post-translational modifications to localise, modulate and ultimately clear DNA repair factors in a timely and accurate manner. Ubiquitination is well established as vital to the DSB response, with a carefully co-ordinated pathway of histone ubiquitination events being a central component of DSB signalling. Other ubiquitin-like modifiers (Ubl) including SUMO and NEDD8 have since been identified as playing important roles in DSB repair. In the last five years ∼20 additional Ub/Ubl proteases have been implicated in the DSB response. The number of proteases identified highlights the complexity of the Ub/Ubl signal present at DSBs. Ub/Ubl proteases regulate turnover, activity and protein–protein interactions of DSB repair factors both catalytically and non-catalytically. This not only ensures efficient repair of breaks but has a role in channelling repair into the correct DSB repair sub-pathways. Ultimately Ub/Ubl proteases have essential roles in maintaining genomic stability. Given that deficiencies in many Ub/Ubl proteases promotes sensitivity to DNA damaging chemotherapies, they could be attractive targets for cancer treatment.

scholarly journals Control of meiotic double-strand-break formation by ATM: local and global views

2017 ◽  
Author(s):  
Agnieszka Lukaszewicz ◽  
Julian Lange ◽  
Scott Keeney ◽  
Maria Jasin
Keyword(s):  
Strand Break ◽  
Double Strand Breaks ◽  
Genome Integrity ◽  
Future Research ◽  
Dna Double Strand Breaks ◽  
Time Loss ◽  
Strand Breaks ◽  
Research Perspectives ◽  
The Right ◽  
Break Formation

ABSTRACTDNA double-strand breaks (DSBs) generated by the SPO11 protein initiate meiotic recombination, an essential process for successful chromosome segregation during gametogenesis. The activity of SPO11 is controlled by multiple factors and regulatory mechanisms, such that the number of DSBs is limited and DSBs form at distinct positions in the genome and at the right time. Loss of this control can affect genome integrity or cause meiotic arrest by mechanisms that are not fully understood. Here we focus on the DSB-responsive kinase ATM and its functions in regulating meiotic DSB numbers and distribution. We review the recently discovered roles of ATM in this context, discuss their evolutionary conservation, and examine future research perspectives.

scholarly journals Regulation of Histone Ubiquitination in Response to DNA Double Strand Breaks

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1699 ◽  
Author(s):  
Lanni Aquila ◽  
Boyko S. Atanassov
Keyword(s):  
Double Strand Breaks ◽  
Deubiquitinating Enzymes ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Comprehensive Overview ◽  
Post Translational Modifications ◽  
Strand Breaks ◽  
Cellular Processes ◽  
Downstream Effectors ◽  
Non Homologous End Joining

Eukaryotic cells are constantly exposed to both endogenous and exogenous stressors that promote the induction of DNA damage. Of this damage, double strand breaks (DSBs) are the most lethal and must be efficiently repaired in order to maintain genomic integrity. Repair of DSBs occurs primarily through one of two major pathways: non-homologous end joining (NHEJ) or homologous recombination (HR). The choice between these pathways is in part regulated by histone post-translational modifications (PTMs) including ubiquitination. Ubiquitinated histones not only influence transcription and chromatin architecture at sites neighboring DSBs but serve as critical recruitment platforms for repair machinery as well. The reversal of these modifications by deubiquitinating enzymes (DUBs) is increasingly being recognized in a number of cellular processes including DSB repair. In this context, DUBs ensure proper levels of ubiquitin, regulate recruitment of downstream effectors, dictate repair pathway choice, and facilitate appropriate termination of the repair response. This review outlines the current understanding of histone ubiquitination in response to DSBs, followed by a comprehensive overview of the DUBs that catalyze the removal of these marks.

Extracellular matrix biology in the lung

1996 ◽  
Vol 270 (1) ◽  
pp. L3-L27 ◽  
Author(s):  
S. E. Dunsmore ◽  
D. E. Rannels
Keyword(s):  
Extracellular Matrix ◽  
Basement Membrane ◽  
Current Knowledge ◽  
Biological Effects ◽  
Alveolar Epithelium ◽  
Basement Membranes ◽  
Model Systems ◽  
Capillary Endothelium ◽  
Future Research ◽  
Membrane Components

The lung and other organs are comprised of both cellular and extracellular compartments. Interaction of these components modulates physiological function at the organ, cellular, and subcellular levels. Extracellular components in the gas-exchange region of the lung include both noncellular interstitium and basement membranes. Connective tissue elements of the interstitium in part determine ventilatory function by contributions to tissue compliance and to resistance of the diffusion barrier. The basement membrane underlies cells of both the alveolar epithelium and the capillary endothelium; basement membrane components exert biological effects on adjacent cells through receptor-mediated interactions. This review emphasizes current knowledge concerning the composition and biological activity of extracellular matrix in the alveolar region of the lung. Matrix synthesis and turnover are also considered. Directions for future research are suggested in the context of current knowledge of the lung and other model systems.

scholarly journals The Biological Significance and Regulatory Mechanism of c-Myc Binding Protein 1 (MBP-1)

2018 ◽  
Vol 19 (12) ◽  
pp. 3868 ◽  
Author(s):  
Zijin Liu ◽  
Aileen Zhang ◽  
Lamei Zheng ◽  
Abou-Fadel Johnathan ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Abiotic Stress ◽  
Stress Responses ◽  
Crop Yields ◽  
Current Knowledge ◽  
Binding Protein ◽  
Biological Significance ◽  
Future Research ◽  
Cervical Cancer Cells ◽  
Integral Role ◽  
Environmental Responses

Alternatively translated from the ENO gene and expressed in an array of vertebrate and plant tissues, c-Myc binding protein 1 (MBP-1) participates in the regulation of growth in organisms, their development and their environmental responses. As a transcriptional repressor of multiple proto-oncogenes, vertebrate MBP-1 interacts with other cellular factors to attenuate the proliferation and metastasis of lung, breast, esophageal, gastric, bone, prostrate, colorectal, and cervical cancer cells. Due to its tumor-suppressive property, MBP-1 and its downstream targets have been investigated as potential prognostic markers and therapeutic targets for various cancers. In plants, MBP-1 plays an integral role in regulating growth and development, fertility and abiotic stress responses. A better understanding of the functions and regulatory factors of MBP-1 in plants may advance current efforts to maximize plant resistance against drought, high salinity, low temperature, and oxidative stress, thus optimizing land use and crop yields. In this review article, we summarize the research advances in biological functions and mechanistic pathways underlying MBP-1, describe our current knowledge of the ENO product and propose future research directions on vertebrate health as well as plant growth, development and abiotic stress responses.

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