1,721,080 research outputs found
POLY(ADP-RIBOSYL)ATION AFFECTS STABILIZATION OF CHE-1 PROTEIN IN RESPONSE TO DNA DAMAGE
Full text linkPost-translation modifications play a crucial role in coordinating the cellular response to DNA damage.
Double strand DNA breaks (DSBs) trigger the activation of ATM and Chk2 kinases, which represent the primary transducers in the signalling cascade. Among the high number of phosphorylated proteins, our attention was focused on Che-1, a novel ATM and Chk2 substrate whose role in DNA damage response has been recently shown. Phosphorylated Che-1 accumulates and promotes transcription of p53 and p53-responsive genes, which are critical for the maintenance of G2 arrest and for DNA repair processes .
Poly(ADP-ribosyl)ation is a post-translational modification that shows an emerging role in the signal transduction to the DDR machinery. Poly(ADP-ribose) polymerase 1 (PARP-1), the main enzyme involved in this modification, is recruited on DNA lesions and catalyzes the synthesis of poly(ADP-ribose) polymers (PAR) on itself and on target proteins. In particular, a recent work demonstrated that PAR synthesis at DSBs sites is necessary to recruit ATM kinase, which can interact non-covalently with PAR.
In this study we showed that poly(ADP-ribosyl)ation, beyond phosphorylation, is involved in the regulation of Che-1 stabilization following DNA damage. We demonstrated that Che-1 accumulation upon doxorubicin treatment is reduced after inhibition of PARP activity in HCT116 cells and in PARP-1 knock-out or silenced cells. In accordance, impairment in Che-1 accumulation by PARP inhibition reduced Che-1 occupancy at p21 promoter and affected the expression of the corresponding gene. Epistasis experiments showed that the effect of poly(ADP-ribosyl)ation on Che-1 stabilization is independent from ATM kinase activity. Indeed we demonstrated that Che-1 protein co-immunoprecipitates with ADP-ribose polymers and that PARP-1 directly interacts with Che-1, promoting its modification in vitro and in vivo.
Altogether, these findings suggest that poly(ADP-ribosyl)ation of Che-1 represents a mechanism enabling the precise control over the level of Che-1 protein in response to DNA damage
Small immunological clocks identified by deep learning and gradient boosting
Full text linkBackground: The aging process affects all systems of the human body, and the observed increase in inflammatory components affecting the immune system in old age can lead to the development of age-associated diseases and systemic inflammation. Results: We propose a small clock model SImAge based on a limited number of immunological biomarkers. To regress the chronological age from cytokine data, we first use a baseline Elastic Net model, gradient-boosted decision trees models, and several deep neural network architectures. For the full dataset of 46 immunological parameters, DANet, SAINT, FT-Transformer and TabNet models showed the best results for the test dataset. Dimensionality reduction of these models with SHAP values revealed the 10 most age-associated immunological parameters, taken to construct the SImAge small immunological clock. The best result of the SImAge model shown by the FT-Transformer deep neural network model has mean absolute error of 6.94 years and Pearson ρ = 0.939 on the independent test dataset. Explainable artificial intelligence methods allow for explaining the model solution for each individual participant. Conclusions: We developed an approach to construct a model of immunological age based on just 10 immunological parameters, coined SImAge, for which the FT-Transformer deep neural network model had proved to be the best choice. The model shows competitive results compared to the published studies on immunological profiles, and takes a smaller number of features as an input. Neural network architectures outperformed gradient-boosted decision trees, and can be recommended in the further analysis of immunological profiles
Origin and evolution of the c.844_845ins68/c.833T>C mutations within the cystathionine β-synthase gene in great apes
No full textAbstractThe c.[833C; 844_845ins68] is a common haplotype of the human cystathionine β-synthase gene among healthy individuals. This polymorphism (5–40% allelic frequency in different populations) consists of the c.844_845ins68 insertion that segregates in cis with the pathogenic c.833T>C substitution (p.I278T). Through genotyping of primates, we have found that gorillas, chimpanzees and bonobos are homozygous for the 68bp insertion, c.844_845ins68. In gorillas and bonobos, the c.844_845ins68 lesion segregates in cis with the wild-type c.833T variant, whilst chimpanzees present the human haplotype. These genetic evidences suggest that the origin of the 68bp insertion might be dated back to 6–8 million years ago, and that the c.833T>C substitution occurred within the allele carrying the insertion. The evolutionary conservation of this peculiar haplotype supports the hypothesis of its protective effects against cardiovascular diseases
The methylation of nuclear and mitochondrial DNA in ageing phenotypes and longevity
No full textAn increasing body of data is progressively indicating that the comprehension of the epigenetic landscape, actively integrated with the genetic elements, is crucial to delineate the molecular basis of the inter-individual complexity of ageing process. Indeed, it has emerged that DNA methylation changes occur during ageing, consisting mainly in a progressive process of genome demethylation, in a hypermethylation of gene-specific CpG dinucleotides, as well as in an inter-individual divergence of the epigenome due to stochastic events and environmental exposures throughout life, namely as epigenetic drift. Additionally, it has also come to light an implication of the mitochondrial genome in the regulation of the intracellular epigenetic landscape, as demonstrated by the being itself object of epigenetic modifications. An overview of DNA methylation changes occurring during ageing process at both nuclear and mitochondrial level will be described in this review, also taking into account the recent and promising data available on the 5-hydroxymethylcytosine
Present and future of anti-ageing epigenetic diets
No full textThe rapid technological advancements achieved in the last years have boosted the progressive identification of age-associated epigenetic changes. These studies not only contribute to shed light on the molecular basis of ageing and age-related diseases but, given the plasticity of epigenetic modifications, also provide the basis for anti-ageing interventions to counteract the onset of age-related diseases. In this review we will discuss nutritional interventions as a promising approach that can positively counteract epigenetic changes associated with ageing and promote the health for the elderly. First, we will give an overview of age-associated epigenetic signatures, focusing on DNA methylation. Then, we will report recent evidences regarding the epigenetic changes induced by nutritional interventions in the adulthood (referred as "epigenetic diets"), such as (i) caloric/dietary restriction, (ii) diet supplementation with nutrients involved in one-carbon metabolism and (iii) diet supplementation with bioactive food components. Attention will be drawn on the limits of current studies and the need of proper human models, such as those provided by the ongoing European project NU-AGE. Finally, we will discuss the potential impact of epigenetic diets on inflammaging and age-related diseases, focusing on cardiovascular disease, highlighting the involvement of epigenetic modifications other than DNA methylation, such as microRNA
ADP-ribose polymers localized on Ctcf-Parp1-Dnmt1 complex prevent methylation of Ctcf target sites
No full textPoly(ADP-ribosyl)ation (PARylation) is involved in the maintaining of genomic methylation pattern through its control of DNA methyltranferase 1 (Dnmt1) activity. Our previous findings indicated the CCCTC binding factor/Ctcf as an important player in the mechanism by which PARylation controls the non methylated status of some CpG rich regions. Ctcf is able to activate Poly (ADP-ribose) polymerase 1 (Parp1) which, in turn, inhibits Dnmt1 activity by ADP-ribose polymers located on Parp1 itself. According to this mechanism, Ctcf may act in preserving the epigenetic pattern at promoters of important housekeeping genes. Data here reported evidence Dnmt1 as a new protein partner of Ctcf. Moreover, we show that Ctcf forms a complex with Dnmt1 and PARylated Parp1 at specific Ctcf target sequences and that PARylation is responsible for the maintaining of the non methylated status of some Ctcf-bound CpGs. All this suggests a mechanism by which Parp1, tethered and activated at specific DNA targets by Ctcf, preserves their methylation free status
Epigenetic Variability across Human Populations: A Focus on DNA Methylation Profiles of the KRTCAP3, MAD1L1 and BRSK2 Genes
Full text linkNatural epigenetic diversity has been suggested as a key mechanism in microevolutionary processes due to its capability to create phenotypic variability within individuals and populations. It constitutes an important reservoir of variation potentially useful for rapid adaptation in response to environmental stimuli. The analysis of population epigenetic structure represents a possible tool to study human adaptation and to identify external factors that are able to naturally shape human DNA methylation variability. The aim of this study is to investigate the dynamics that create epigenetic diversity between and within different human groups. To this end, we first used publicly available epigenome-wide data to explore population-specific DNA methylation changes that occur at macro-geographic scales. Results from this analysis suggest that nutrients, UVA exposure and pathogens load might represent the main environmental factors able to shape DNA methylation profiles. Then, we evaluated DNA methylation of candidate genes (KRTCAP3, MAD1L1, and BRSK2), emerged from the previous analysis, in individuals belonging to different populations from Morocco, Nigeria, Philippines, China, and Italy, but living in the same Italian city. DNA methylation of the BRSK2 gene is significantly different between Moroccans and Nigerians (pairwise t-test: CpG 6 P-value = 5.2*10 (-) (3); CpG 9 P-value = 2.6*10 (-) (3); CpG 10 P-value = 3.1*10 (-) (3); CpG 11 P-value = 2.8*10 (-) (3)). Comprehensively, these results suggest that DNA methylation diversity is a source of variability in human groups at macro and microgeographical scales and that population demographic and adaptive histories, as well as the individual ancestry, actually influence DNA methylation profiles
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