Nuclear Genomic Instability and Aging

2018 ◽  
Vol 87 (1) ◽  
pp. 295-322 ◽  
Author(s):  
Laura J. Niedernhofer ◽  
Aditi U. Gurkar ◽  
Yinsheng Wang ◽  
Jan Vijg ◽  
Jan H.J. Hoeijmakers ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Nuclear Dna ◽  
Nuclear Genome ◽  
Accelerated Aging ◽  
Genotoxic Stress ◽  
Dna Lesions ◽  
Age Related ◽  
Damage Accrual ◽  
Theory Of Aging

The nuclear genome decays as organisms age. Numerous studies demonstrate that the burden of several classes of DNA lesions is greater in older mammals than in young mammals. More challenging is proving this is a cause rather than a consequence of aging. The DNA damage theory of aging, which argues that genomic instability plays a causal role in aging, has recently gained momentum. Support for this theory stems partly from progeroid syndromes in which inherited defects in DNA repair increase the burden of DNA damage leading to accelerated aging of one or more organs. Additionally, growing evidence shows that DNA damage accrual triggers cellular senescence and metabolic changes that promote a decline in tissue function and increased susceptibility to age-related diseases. Here, we examine multiple lines of evidence correlating nuclear DNA damage with aging. We then consider how, mechanistically, nuclear genotoxic stress could promote aging. We conclude that the evidence, in toto, supports a role for DNA damage as a nidus of aging.

scholarly journals Intracellular and Intercellular Signalling Mechanisms following DNA Damage Are Modulated By PINK1

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Mihaela Temelie ◽  
Diana Iulia Savu ◽  
Nicoleta Moisoi
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dysfunction ◽  
Cellular Response ◽  
Genotoxic Stress ◽  
Cell System ◽  
Dna Lesions ◽  
Loss Of Function ◽  
Adaptive Responses ◽  
Age Related ◽  
Intercellular Signalling

Impaired mitochondrial function and accumulation of DNA damage have been recognized as hallmarks of age-related diseases. Mitochondrial dysfunction initiates protective signalling mechanisms coordinated at nuclear level particularly by modulating transcription of stress signalling factors. In turn, cellular response to DNA lesions comprises a series of interconnected complex protective pathways, which require the energetic and metabolic support of the mitochondria. These are involved in intracellular as well as in extracellular signalling of damage. Here, we have initiated a study that addresses how mitochondria-nucleus communication may occur in conditions of combined mitochondrial dysfunction and genotoxic stress and what are the consequences of this interaction on the cell system. In this work, we used cells deficient for PINK1, a mitochondrial kinase involved in mitochondrial quality control whose loss of function leads to the accumulation of dysfunctional mitochondria, challenged with inducers of DNA damage, namely, ionizing radiation and the radiomimetic bleomycin. Combined stress at the level of mitochondria and the nucleus impairs both mitochondrial and nuclear functions. Our findings revealed exacerbated sensibility to genotoxic stress in PINK1-deficient cells. The same cells showed an impaired induction of bystander phenomena following stress insults. However, these cells responded adaptively when a challenge dose was applied subsequently to a low-dose treatment to the cells. The data demonstrates that PINK1 modulates intracellular and intercellular signalling pathways, particularly adaptive responses and transmission of bystander signalling, two facets of the cell-protective mechanisms against detrimental agents.

scholarly journals Exifone is a Potent HDAC1 Activator with Neuroprotective Activity in Human Neuronal Models of Neurodegeneration

2020 ◽  
Author(s):  
Debasis Patnaik ◽  
Ping-Chieh Pao ◽  
Wen-Ning Zhao ◽  
M. Catarina Silva ◽  
Norma K. Hylton ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Induced Pluripotent Stem Cell ◽  
Critical Factor ◽  
Genotoxic Stress ◽  
Neuronal Model ◽  
Class I ◽  
Neuroprotective Activity ◽  
Age Related ◽  
Neuroprotective Therapy

AbstractGenomic instability caused by a deficiency in the DNA damage response and repair has been linked to age-related cognitive decline and neurodegenerative diseases. Preventing genomic instability that ultimately leads to neuronal death may provide a broadly effective strategy to protect against multiple potential genotoxic stressors. Recently, the zinc-dependent, class I histone deacetylase HDAC1 has been identified as a critical factor for protecting neurons from deleterious effects of DNA damage in Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Translating these observations to a novel neuroprotective therapy for AD, ALS, and FTD may be advanced by the identification of small molecules capable of increasing the deacetylase activity of HDAC1 selectively over other structurally similar HDACs. Here, we demonstrate that exifone, a drug previously shown to be effective in treating cognitive deficits associated with AD and Parkinson’s disease, the molecular mechanism of which has remained poorly understood, potently activates the deacetylase activity of HDAC1 and provides protection against genotoxic stress. We show that exifone acts as a mixed, non-essential activator of HDAC1 that is capable of binding to both free and substrate-bound enzyme resulting in an increased relative maximal rate of HDAC1-catalyzed deacetylation. Exifone can directly bind to HDAC1 based upon biolayer interferometry assays with kinetic and selectivity profiling suggesting HDAC1 is preferentially targeted compared to other class I HDACs and the kinase CDK5 that have also been implicated in neurodegeneration. Consistent with a mechanism of deacetylase activation intracellularly, treatment of human induced pluripotent stem cell (iPSC)-derived neuronal cells resulted in globally decreased histone acetylation. Moreover, exifone treatment was neuroprotective in a tauopathy patient iPSC-derived neuronal model subject to oxidative stress. Taken together, these findings reveal exifone as a potent activator of HDAC1-mediated deacetylation, thereby offering a lead for novel therapeutic development aiming to protect genomic integrity in the context of neurodegeneration and aging.Graphical Abstract

scholarly journals Lifelong Cytomegalovirus and Early-Life Irradiation Synergistically Potentiate Age-Related Defects in Response to Vaccination and Infection

2021 ◽  
Author(s):  
Jason L. Pugh ◽  
Christopher P. Coplen ◽  
Alona S. Sukhina ◽  
Jennifer L. Uhrlaub ◽  
Jose Padilla-Torres ◽  
...  
Keyword(s):  
Dna Damage ◽  
Early Life ◽  
Acute Infection ◽  
Late Life ◽  
Whole Body ◽  
Murine Cytomegalovirus ◽  
Live Attenuated Vaccine ◽  
Age Related ◽  
Theory Of Aging ◽  
High Level

ABSTRACTA popular “DNA-damage theory” of aging posits that unrepaired DNA damage leads to cellular (and organismal) senescence. Indeed, some hallmarks of immune aging are more prevalent in individuals exposed to Whole-Body Irradiation (WBI). To test this hypothesis in a model relevant to human immune aging, we examined separate and joint effects of lifelong latent Murine Cytomegalovirus (MCMV) and early-life WBI (i) over the course of the lifespan; (ii) in response to a West Nile virus (WNV) live attenuated vaccine; and (iii) following lethal WNV challenge subsequent to vaccination. We recently published that a single dose of non-lethal WBI in youth, on its own, was not sufficient to accelerate aging of the murine immune system despite causing widespread DNA damage and repopulation stress in hematopoietic cells. However, 4Gy sub-lethal WBI caused manifest reactivation of MCMV. Following vaccination and challenge with WNV in the old age, MCMV-infected animals experiencing 4Gy, but not lower, dose of sub-lethal WBI in youth had reduced survival. By contrast, old irradiated mice lacking MCMV and MCMV-infected, but not irradiated, mice were both protected to the same high level as the old non-irradiated, uninfected controls. Analysis of the quality and quantity of anti-WNV immunity showed that higher mortality in MCMV-positive WBI mice correlated with increased levels of MCMV-specific immune activation during WNV challenge. Moreover, we demonstrate that infection, including that by WNV, led to MCMV reactivation. Our data suggest that MCMV reactivation may be an important determinant of increased late-life mortality following early-life irradiation and late-life acute infection.

scholarly journals MORC2 regulates DNA damage response through a PARP1-dependent pathway

2019 ◽  
Vol 47 (16) ◽  
pp. 8502-8520 ◽  
Author(s):  
Lin Zhang ◽  
Da-Qiang Li
Keyword(s):  
Dna Damage ◽  
Zinc Finger ◽  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Genotoxic Stress ◽  
Underlying Mechanism ◽  
Dna Lesions ◽  
Damage Response

Abstract Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling enzyme with an emerging role in DNA damage response (DDR), but the underlying mechanism remains largely unknown. Here, we show that poly(ADP-ribose) polymerase 1 (PARP1), a key chromatin-associated enzyme responsible for the synthesis of poly(ADP-ribose) (PAR) polymers in mammalian cells, interacts with and PARylates MORC2 at two residues within its conserved CW-type zinc finger domain. Following DNA damage, PARP1 recruits MORC2 to DNA damage sites and catalyzes MORC2 PARylation, which stimulates its ATPase and chromatin remodeling activities. Mutation of PARylation residues in MORC2 results in reduced cell survival after DNA damage. MORC2, in turn, stabilizes PARP1 through enhancing acetyltransferase NAT10-mediated acetylation of PARP1 at lysine 949, which blocks its ubiquitination at the same residue and subsequent degradation by E3 ubiquitin ligase CHFR. Consequently, depletion of MORC2 or expression of an acetylation-defective PARP1 mutant impairs DNA damage-induced PAR production and PAR-dependent recruitment of DNA repair proteins to DNA lesions, leading to enhanced sensitivity to genotoxic stress. Collectively, these findings uncover a previously unrecognized mechanistic link between MORC2 and PARP1 in the regulation of cellular response to DNA damage.

scholarly journals Involvement of POLA2 in Double Strand Break Repair and Genotoxic Stress

2020 ◽  
Vol 21 (12) ◽  
pp. 4245
Author(s):  
Tuyen T. Dang ◽  
Julio C. Morales
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Dna Polymerase ◽  
Genotoxic Stress ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Dsb Repair ◽  
Dna Polymerase Alpha ◽  
Break Repair

Cellular survival is dependent on the efficient replication and transmission of genomic information. DNA damage can be introduced into the genome by several different methods, one being the act of DNA replication. Replication is a potent source of DNA damage and genomic instability, especially through the formation of DNA double strand breaks (DSBs). DNA polymerase alpha is responsible for replication initiation. One subunit of the DNA polymerase alpha replication machinery is POLA2. Given the connection between replication and genomic instability, we decided to examine the role of POLA2 in DSB repair, as little is known about this topic. We found that loss of POLA2 leads to an increase in spontaneous DSB formation. Loss of POLA2 also slows DSB repair kinetics after treatment with etoposide and inhibits both of the major double strand break repair pathways: non-homologous end-joining and homologous recombination. In addition, loss of POLA2 leads to increased sensitivity to ionizing radiation and PARP1 inhibition. Lastly, POLA2 expression is elevated in glioblastoma multiforme tumors and correlates with poor overall patient survival. These data demonstrate a role for POLA2 in DSB repair and resistance to genotoxic stress.

scholarly journals Mitochondrial and Nuclear DNA Damage and Repair in Age-Related Macular Degeneration

2013 ◽  
Vol 14 (2) ◽  
pp. 2996-3010 ◽  
Author(s):  
Janusz Blasiak ◽  
Sylwester Glowacki ◽  
Anu Kauppinen ◽  
Kai Kaarniranta
Keyword(s):  
Dna Damage ◽  
Macular Degeneration ◽  
Nuclear Dna ◽  
Age Related Macular Degeneration ◽  
Dna Damage And Repair ◽  
Age Related

scholarly journals Transcriptional profiling of the age-related response to genotoxic stress points to differential DNA damage response with age

2009 ◽  
Vol 130 (9) ◽  
pp. 637-647 ◽  
Author(s):  
Kirk Simon ◽  
Anju Mukundan ◽  
Samantha Dewundara ◽  
Holly Van Remmen ◽  
Alan A. Dombkowski ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Transcriptional Profiling ◽  
Genotoxic Stress ◽  
Age Related ◽  
Damage Response ◽  
Related Response

scholarly journals Supraphysiological protection from replication stress does not extend mammalian lifespan

2020 ◽  
Author(s):  
Eliene Albers ◽  
Alexandra Avram ◽  
Mauro Sbroggio ◽  
Oscar Fernandez-Capetillo ◽  
Andres J Lopez-Contreras
Keyword(s):  
Dna Damage ◽  
Transgenic Mice ◽  
Genomic Instability ◽  
Genetic Background ◽  
Replication Fork ◽  
Accelerated Aging ◽  
Replication Stress ◽  
Term Survival ◽  
Survival Studies

AbstractReplication Stress (RS) is a type of DNA damage generated at the replication fork, characterized by single-stranded DNA (ssDNA) accumulation, and which can be caused by a variety of factors. Previous studies have reported elevated RS levels in aged cells. In addition, mouse models with a deficient RS response show accelerated aging. However, the relevance of endogenous or physiological RS, compared to other sources of genomic instability, for the normal onset of aging is unknown. We have performed long term survival studies of transgenic mice with extra copies of the Chk1 and/or Rrm2 genes, which we previously showed extend the lifespan of a progeroid ATR-hypomorphic model suffering from high levels of RS. In contrast to their effect in the context of progeria, the lifespan of Chk1, Rrm2 and Chk1/Rrm2 transgenic mice was similar to WT littermates in physiological settings. Most mice studied died due to tumors -mainly lymphomas-irrespective of their genetic background. Interestingly, a slightly higher percentage of transgenic mice developed tumors compared to WT mice. Our results indicate that supraphysiological protection from RS does not extend lifespan, indicating that RS may not be a relevant source of genomic instability on the onset of “normal” aging.

scholarly journals DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Chiara Milanese ◽  
Cíntia R. Bombardieri ◽  
Sara Sepe ◽  
Sander Barnhoorn ◽  
César Payán-Goméz ◽  
...  
Keyword(s):  
Dna Damage ◽  
Excision Repair ◽  
Accelerated Aging ◽  
Pentose Phosphate ◽  
Dna Lesions ◽  
Antioxidant Defenses ◽  
Knock Out ◽  
Transcriptional Stress ◽  
Knock Out Mice ◽  
Enhancing Production

Abstract Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels. This in turn inhibits glycolysis allosterically and favors glucose rerouting through the pentose phosphate shunt, eventually enhancing production of NADPH-reducing equivalents. In NER/TCR-defective mutants, augmented NADPH is not counterbalanced by increased production of pro-oxidants and thus pentose phosphate potentiation culminates in an over-reduced redox state. Skin fibroblasts from the TCR disease Cockayne syndrome confirm results in animal models. Overall, these findings unravel a mechanism connecting DNA damage and transcriptional stress to metabolic redesign and protective antioxidant defenses.

BCR/ABL Expression Increases the Formation of Chromosomal Translocations after DNA Damage.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 713-713 ◽  
Author(s):  
Jamil Dierov ◽  
Hesed Padilla-Nash ◽  
Thomas Ried ◽  
Martin Carroll
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Cellular Response ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Annexin V ◽  
Genotoxic Stress ◽  
Protein Product ◽  
Chromosomal Translocations ◽  
Dna Double Strand Breaks

Abstract BCR/ABL is the protein product of the t(9;22) translocation and is the cause of the hyperproliferation associated with chronic phase chronic myeloid leukemia (CML). However, whether BCR/ABL induces genomic instability leading to blast crisis is controversial. We have previously demonstrated that BCR/ABL translocates to the nucleus after genotoxic damage and associates with the DNA damage sensor, ataxia telangiectasia and rad 3 related (ATR) protein, disrupting the sensing and repair of DNA double strand breaks. Here, we have asked if BCR/ABL expression leads to permanent changes in the DNA after genotoxic stress. For these experiments we have studied the hematopoietic cell line, Ba/F3pTetOn p210, which expresses p210 BCR/ABL after incubation in doxycycline. Cells were incubated in low doses of etoposide for two hours and then allowed to recover for 48 hours in the absence of further DNA damage. Induction of apoptosis in these conditions was consistently less than 5% as demonstrated by annexin V staining of cells. Cells were examined for alterations in the chromosomes using Giemsa banding and spectral karyotyping (SKY). Cells growing in IL3 showed low levels of DNA damage with a few broken chromosomes present in metaphase spreads and an average of 0.5 new chromosomal translocations per cell as revealed by SKY analysis. In contrast, when cells expressing BCR/ABL were treated with the same conditions, a marked number of genetic abnormalities were seen. 75% of cells showed abnormal chromosome forms with ring chromosomes, triradial forms and other abnormalitites. Analysis of BCR/ABL expressing cells by SKY analysis showed frequent abnormalities, averaging at least 6 new translocations per cell. Several cells had greater than 10 translocations present including multiple complex translocations involving more than two chromosomes. The majority of abnormalities consisted of unbalanced translocations. This data demonstrates that BCR/ABL alters the cellular response to DNA damage leading to an increase in chromosomal translocations in cells expressing the oncogene and suggests that BCR/ABL itself is directly responsible for the genomic instability leading to CML blast crisis.

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