Increase in double-stranded DNA break-related foci in early-stage thymocytes of aged mice

Hesse, Jill E.; Faulkner, Matthew F; Durdik, Jeannine M.

doi:10.1016/j.exger.2009.06.009

Cited by 5 publications

(3 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a seminal paper [ 5 ], senescing human cells of various origins (normal and WI38 fibroblasts, PrEC: prostate epithelial cells) and five mouse organs (liver, testis, kidney, lung and brain) were shown to display increased levels of H2AX phosphorylation. These observations were subsequently, confirmed and/or extended [ 6 – 9 ], and, in parallel, γH2AX was described in various types of tumors entering the scene of clinical research and therapy in oncology [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 80%

Phosphorylation of Histone H2AX in the Mouse Brain from Development to Senescence

Barral

Beltramo

Salio

et al. 2014

IJMS

View full text Add to dashboard Cite

Phosphorylation of the histone H2AX (γH2AX form) is an early response to DNA damage and a marker of aging and disease in several cells and tissues outside the nervous system. Little is known about in vivo phosphorylation of H2AX in neurons, although it was suggested that γH2AX is an early marker of neuronal endangerment thus opening the possibility to target it as a neuroprotective strategy. After experimental labeling of DNA-synthesizing cells with 5-bromo-2-deoxyuridine (BrdU), we studied the brain occurrence of γH2AX in developing, postnatal, adult and senescent (2 years) mice by light and electron microscopic immunocytochemistry and Western blotting. Focal and/or diffuse γH2AX immunostaining appears in interkinetic nuclei, mitotic chromosomes, and apoptotic nuclei. Immunoreactivity is mainly associated with neurogenetic areas, i.e., the subventricular zone (SVZ) of telencephalon, the cerebellar cortex, and, albeit to a much lesser extent, the subgranular zone of the hippocampal dentate gyrus. In addition, γH2AX is highly expressed in the adult and senescent cerebral cortex, particularly the piriform cortex. Double labeling experiments demonstrate that γH2AX in neurogenetic brain areas is temporally and functionally related to proliferation and apoptosis of neuronal precursors, i.e., the type C transit amplifying cells (SVZ) and the granule cell precursors (cerebellum). Conversely, γH2AX-immunoreactive cortical neurons incorporating the S phase-label BrdU do not express the proliferation marker phosphorylated histone H3, indicating that these postmitotic cells undergo a significant DNA damage response. Our study paves the way for a better comprehension of the role of H2AX phosphorylation in the normal brain, and offers additional data to design novel strategies for the protection of neuronal precursors and mature neurons in central nervous system (CNS) degenerative diseases.

show abstract

Section: Introductionmentioning

confidence: 80%

Phosphorylation of Histone H2AX in the Mouse Brain from Development to Senescence

Barral

Beltramo

Salio

et al. 2014

IJMS

View full text Add to dashboard Cite

show abstract

“…However, gene rearrangement in developing lymphocytes occurs via non-homologous end joining pathway, which is relatively insensitive to dNTP levels [77] . Anabolic demands of major proliferative expansion result in increased metabolic activity, accumulation of reactive oxygen species and DNA damage [78] . It remains unclear whether dCK activation above baseline is needed to meet the demands of DNA replication and/or repair in the developing lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Deoxycytidine Kinase Augments ATM-Mediated DNA Repair and Contributes to Radiation Resistance

et al. 2014

View full text Add to dashboard Cite

Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response to ionizing radiation (IR). Activation of dCK shifts its substrate specificity toward deoxycytidine, increases intracellular dCTP pools post IR, and enhances the rate of DNA repair. Mutation of a single serine 74 residue has profound effects on murine T and B lymphocyte development, suggesting that post-translational regulation of dCK may be important in maintaining genomic stability during hematopoiesis. Using [18F]-FAC, a dCK-specific positron emission tomography (PET) probe, we visualized and quantified dCK activation in tumor xenografts after IR, indicating that dCK activation could serve as a biomarker for ATM function and DNA damage response in vivo. In addition, dCK-deficient leukemia cell lines and murine embryonic fibroblasts exhibited increased sensitivity to IR, indicating that pharmacologic inhibition of dCK may be an effective radiosensitization strategy.

show abstract

“…Indeed, the impact of cellular senescence on ageing of organisms was previously evaluated in different studies revealing an accumulation of DNA damage in both senescent cells and ageing organisms (Sedelnikova et al, 2008). In particular, several works described accumulated ␥H2AX foci, which reveal persistent DNA double-stranded breaks, in senescing human cell cultures and in ageing mice (Sedelnikova et al, 2004), in early thymocyte subsets of aged as compared to young mice (Hesse et al, 2009), in different organs from ageing C57Bl6 mice (Wang et al, 2009) and in fibroblasts taken from patients with Werner syndrome (Sedelnikova et al, 2008).…”

Section: Dna Repair Abilitymentioning

confidence: 99%

Oxidative stress, genomic features and DNA repair in frail elderly: A systematic review

Sánchez-Flores

Marcos-Pérez

Costa

et al. 2017

Ageing Research Reviews

View full text Add to dashboard Cite

Frailty is an emerging geriatric syndrome characterized by higher vulnerability to stressors, with an increased risk of adverse health outcomes such as mortality, morbidity, disability, hospitalization, and institutionalization. Although it is generally recognized to have a biological basis, no particular biological trait has been consistently associated to frailty status so far. In this work, epidemiological studies evaluating association of frailty status with alterations at cellular level - namely oxidative stress, genomic instability and DNA damage and repair biomarkers -were revised and compared. A total of 25 studies fulfilled inclusion/exclusion criteria and, consequently, were included in the review. Variations of oxidative stress biomarkers were often associated to frailty status in older people. On the contrary, genomic instability seems not to be linked to frailty. The only study which addressed the possible relationship between DNA repair modulations and frailty status also failed in finding association. Despite the large number of cellular alterations known to be associated with frailty, studies on this issue are still very scarce and limited to some of the possible cellular targets. The established link between DNA repair, genomic instability, and age and age-related disorders, encourage deeper investigations on this line.

show abstract

Increase in double-stranded DNA break-related foci in early-stage thymocytes of aged mice

Cited by 5 publications

References 39 publications

Phosphorylation of Histone H2AX in the Mouse Brain from Development to Senescence

Phosphorylation of Histone H2AX in the Mouse Brain from Development to Senescence

Deoxycytidine Kinase Augments ATM-Mediated DNA Repair and Contributes to Radiation Resistance

Oxidative stress, genomic features and DNA repair in frail elderly: A systematic review

Contact Info

Product

Resources

About