scholarly journals Multifunctional Role of ATM/Tel1 Kinase in Genome Stability: From the DNA Damage Response to Telomere Maintenance

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Enea Gino Di Domenico ◽  
Elena Romano ◽  
Paola Del Porto ◽  
Fiorentina Ascenzioni
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Genome Stability ◽  
Genetic Disorder ◽  
Cell Cycle Control ◽  
Premature Aging ◽  
Telomere Maintenance ◽  
Damage Response

The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere maintenance and length regulation. Likewise, inSaccharomyces cerevisiae, haploid strains defective in theTEL1gene, the ATM ortholog, show chromosomal aberrations and short telomeres. In this review, we outline the complex role of ATM/Tel1 in maintaining genomic stability through its control of numerous aspects of cellular survival. In particular, we describe how ATM/Tel1 participates in the signal transduction pathways elicited by DNA damage and in telomere homeostasis and its importance as a barrier to cancer development.

scholarly journals Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD

2012 ◽  
Vol 303 (7) ◽  
pp. L557-L566 ◽  
Author(s):  
Hongwei Yao ◽  
Irfan Rahman
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Premature Aging ◽  
Epigenetic Mechanism ◽  
Histone Deacetylase 2 ◽  
Damage Response

Histone deacetylase 2 (HDAC2) is a class I histone deacetylase that regulates various cellular processes, such as cell cycle, senescence, proliferation, differentiation, development, apoptosis, and glucocorticoid function in inhibiting inflammatory response. HDAC2 has been shown to protect against DNA damage response and cellular senescence/premature aging via an epigenetic mechanism in response to oxidative stress. These phenomena are observed in patients with chronic obstructive pulmonary disease (COPD). HDAC2 is posttranslationally modified by oxidative/carbonyl stress imposed by cigarette smoke and oxidants, leading to its reduction via an ubiquitination-proteasome dependent degradation in lungs of patients with COPD. In this perspective, we have discussed the role of HDAC2 posttranslational modifications and its role in regulation of inflammation, histone/DNA epigenetic modifications, DNA damage response, and cellular senescence, particularly in inflammaging, and during the development of COPD. We have also discussed the potential directions for future translational research avenues in modulating lung inflammaging and cellular senescence based on epigenetic chromatin modifications in diseases associated with increased oxidative stress.

scholarly journals Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Julio Aguado ◽  
Agustin Sola-Carvajal ◽  
Valeria Cancila ◽  
Gwladys Revêchon ◽  
Peh Fern Ong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Genetic Disorder ◽  
Premature Aging ◽  
Telomere Dysfunction ◽  
Damage Response ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

AbstractHutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.

scholarly journals 53BP1 deficiency combined with telomere dysfunction activates ATR-dependent DNA damage response

2012 ◽  
Vol 197 (2) ◽  
pp. 283-300 ◽  
Author(s):  
Paula Martínez ◽  
Juana M. Flores ◽  
Maria A. Blasco
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Homology Directed Repair ◽  
Damage Response

TRF1 protects mammalian telomeres from fusion and fragility. Depletion of TRF1 leads to telomere fusions as well as accumulation of γ-H2AX foci and activation of both the ataxia telangiectasia mutated (ATM)– and the ataxia telangiectasia and Rad3 related (ATR)–mediated deoxyribonucleic acid (DNA) damage response (DDR) pathways. 53BP1, which is also present at dysfunctional telomeres, is a target of ATM that accumulates at DNA double-strand breaks and favors nonhomologous end-joining (NHEJ) repair over ATM-dependent resection and homology-directed repair (homologous recombination [HR]). To address the role of 53BP1 at dysfunctional telomeres, we generated mice lacking TRF1 and 53BP1. 53BP1 deficiency significantly rescued telomere fusions in mouse embryonic fibroblasts (MEFs) lacking TRF1, but they showed evidence of a switch from the NHEJ- to HR-mediated repair of uncapped telomeres. Concomitantly, double-mutant MEFs showed evidence of hyperactivation of the ATR-dependent DDR. In intact mice, combined 53BP1/TRF1 deficiency in stratified epithelia resulted in earlier onset of DNA damage and increased CHK1 phosphorylation during embryonic development, leading to aggravation of skin phenotypes.

The p53 response during DNA damage: impact of transcriptional cofactors

2006 ◽  
Vol 73 ◽  
pp. 181-189 ◽  
Author(s):  
Amanda S. Coutts ◽  
Nicholas La Thangue
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Cell Cycle Control ◽  
Regulatory Protein ◽  
Serine Threonine Kinase ◽  
Receptor Associated Protein ◽  
Transcriptional Cofactors ◽  
Damage Response ◽  
P53 Response

Defects in the DNA damage response pathways can lead to tumour development. The tumour suppressor p53 is a key player in the DNA damage response, and the precise regulation of p53 is critical for the suppression of tumorigenesis. DNA damage induces the activity of p53, via damage sensors such as ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia-related), which leads to the transcriptional regulation of a variety of genes involved in cell cycle control and apoptosis. p53 is therefore tightly controlled, and its activity is regulated at a multiplicity of levels. An increasing array of cofactors are now known to influence p53 activity. Here we will discuss several of the cofactors that impact on p53 activity, specifically those involved in the function of the two novel p53 cofactors JMY (junction-mediating and regulatory protein) and Strap (serine/threonine-kinase-receptor-associated protein).

Maintenance of genome stability: the unifying role of interconnections between the DNA damage response and RNA-processing pathways

2018 ◽  
Vol 64 (5) ◽  
pp. 971-983 ◽  
Author(s):  
B. Mikolaskova ◽  
M. Jurcik ◽  
I. Cipakova ◽  
M. Kretova ◽  
M. Chovanec ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Rna Processing ◽  
Genome Stability ◽  
Damage Response ◽  
Processing Pathways

scholarly journals On Broken Ne(c)ks and Broken DNA: The Role of Human NEKs in the DNA Damage Response

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 507
Author(s):  
Isadora Carolina Betim Pavan ◽  
Andressa Peres de Oliveira ◽  
Pedro Rafael Firmino Dias ◽  
Fernanda Luisa Basei ◽  
Luidy Kazuo Issayama ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
General Role ◽  
Cycle Arrest ◽  
Damage Response ◽  
Repair Pathways

NIMA-related kinases, or NEKs, are a family of Ser/Thr protein kinases involved in cell cycle and mitosis, centrosome disjunction, primary cilia functions, and DNA damage responses among other biological functional contexts in vertebrate cells. In human cells, there are 11 members, termed NEK1 to 11, and the research has mainly focused on exploring the more predominant roles of NEKs in mitosis regulation and cell cycle. A possible important role of NEKs in DNA damage response (DDR) first emerged for NEK1, but recent studies for most NEKs showed participation in DDR. A detailed analysis of the protein interactions, phosphorylation events, and studies of functional aspects of NEKs from the literature led us to propose a more general role of NEKs in DDR. In this review, we express that NEK1 is an activator of ataxia telangiectasia and Rad3-related (ATR), and its activation results in cell cycle arrest, guaranteeing DNA repair while activating specific repair pathways such as homology repair (HR) and DNA double-strand break (DSB) repair. For NEK2, 6, 8, 9, and 11, we found a role downstream of ATR and ataxia telangiectasia mutated (ATM) that results in cell cycle arrest, but details of possible activated repair pathways are still being investigated. NEK4 shows a connection to the regulation of the nonhomologous end-joining (NHEJ) repair of DNA DSBs, through recruitment of DNA-PK to DNA damage foci. NEK5 interacts with topoisomerase IIβ, and its knockdown results in the accumulation of damaged DNA. NEK7 has a regulatory role in the detection of oxidative damage to telomeric DNA. Finally, NEK10 has recently been shown to phosphorylate p53 at Y327, promoting cell cycle arrest after exposure to DNA damaging agents. In summary, this review highlights important discoveries of the ever-growing involvement of NEK kinases in the DDR pathways. A better understanding of these roles may open new diagnostic possibilities or pharmaceutical interventions regarding the chemo-sensitizing inhibition of NEKs in various forms of cancer and other diseases.

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