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Nature Communications Aug 2023Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication...
Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. Over the years, TRAIP E3 ubiquitin ligase has been shown to play a role in various cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability, and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells and to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We conclude that upon rapid TRAIP degradation, specifically in S-phase, cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. Our findings reveal that TRAIP works in S-phase to prevent DNA damage at transcription start sites, caused by replication-transcription conflicts.
Topics: Humans; S Phase; Cell Division; Cell Proliferation; Cell Cycle; Cell Survival; Ubiquitin-Protein Ligases
PubMed: 37604812
DOI: 10.1038/s41467-023-40695-y -
Frontiers in Endocrinology 2023The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway emerged in recent years as a key determinant of aging and longevity. Disruption of this... (Review)
Review
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway emerged in recent years as a key determinant of aging and longevity. Disruption of this network in different animal species, including flies, nematodes and mouse, was consistently associated with an extended lifespan. Epidemiological analyses have shown that patients with Laron syndrome (LS), the best-characterized disease under the umbrella of the congenital IGF1 deficiencies, seem to be protected from cancer. While aging and cancer, as a rule, are considered diametrically opposite processes, modern lines of evidence reinforce the notion that aging and cancer might, as a matter of fact, be regarded as divergent manifestations of identical biochemical and cellular underlying processes. While the effect of individual mutations on lifespan and health span is very difficult to assess, genome-wide screenings identified a number of differentially represented aging- and longevity-associated genes in patients with LS. The present review summarizes recent data that emerged from comprehensive analyses of LS patients and portrays a number of previously unrecognized targets for GH-IGF1 action. Our article sheds light on complex aging and longevity processes, with a particular emphasis on the role of the GH-IGF1 network in these mechanisms.
Topics: Humans; Mice; Animals; Laron Syndrome; Aging; Longevity; Growth Hormone; Human Growth Hormone; Neoplasms
PubMed: 37941907
DOI: 10.3389/fendo.2023.1291812 -
Aging Cell Oct 2023Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS) are rare genetic disorders caused by mutation of the DNA repair and multifunctional CSA or CSB protein, but only...
Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS) are rare genetic disorders caused by mutation of the DNA repair and multifunctional CSA or CSB protein, but only CS patients display a progeroid and neurodegenerative phenotype, providing a unique conceptual and experimental paradigm. As DNA methylation (DNAm) remodelling is a major ageing marker, we performed genome-wide analysis of DNAm of fibroblasts from healthy, UVSS and CS individuals. Differential analysis highlighted a CS-specific epigenomic signature (progeroid-related; not present in UVSS) enriched in three categories: developmental transcription factors, ion/neurotransmitter membrane transporters and synaptic neuro-developmental genes. A large fraction of CS-specific DNAm changes were associated with expression changes in CS samples, including in previously reported post-mortem cerebella. The progeroid phenotype of CS was further supported by epigenomic hallmarks of ageing: the prediction of DNAm of repetitive elements suggested an hypomethylation of Alu sequences in CS, and the epigenetic clock returned a marked increase in CS biological age respect to healthy and UVSS cells. The epigenomic remodelling of accelerated ageing in CS displayed both commonalities and differences with other progeroid diseases and regular ageing. CS shared DNAm changes with normal ageing more than other progeroid diseases do, and included genes functionally validated for regular ageing. Collectively, our results support the existence of an epigenomic basis of accelerated ageing in CS and unveil new genes and pathways that are potentially associated with the progeroid/degenerative phenotype.
Topics: Humans; Cockayne Syndrome; Epigenomics; DNA Repair Enzymes; DNA Repair; Aging; Mutation
PubMed: 37688320
DOI: 10.1111/acel.13959 -
Bone Research Aug 2023Endochondral ossification requires proper control of chondrocyte proliferation, differentiation, survival, and organization. Here we show that knockout of α-parvin, an...
Endochondral ossification requires proper control of chondrocyte proliferation, differentiation, survival, and organization. Here we show that knockout of α-parvin, an integrin-associated focal adhesion protein, from murine limbs causes defects in endochondral ossification and dwarfism. The mutant long bones were shorter but wider, and the growth plates became disorganized, especially in the proliferative zone. With two-photon time-lapse imaging of bone explant culture, we provide direct evidence showing that α-parvin regulates chondrocyte rotation, a process essential for chondrocytes to form columnar structure. Furthermore, loss of α-parvin increased binucleation, elevated cell death, and caused dilation of the resting zones of mature growth plates. Single-cell RNA-seq analyses revealed alterations of transcriptome in all three zones (i.e., resting, proliferative, and hypertrophic zones) of the growth plates. Our results demonstrate a crucial role of α-parvin in long bone development and shed light on the cellular mechanism through which α-parvin regulates the longitudinal growth of long bones.
Topics: Animals; Mice; Bone Development; Cell Death; Chondrocytes; Growth Plate; Osteogenesis
PubMed: 37607905
DOI: 10.1038/s41413-023-00284-7 -
Aging Aug 2023
Topics: Humans; Aging; Cockayne Syndrome; Epigenesis, Genetic; DNA Methylation
PubMed: 37552095
DOI: 10.18632/aging.204977 -
Frontiers in Endocrinology 2024
Topics: Humans; Dwarfism; Human Growth Hormone
PubMed: 38606084
DOI: 10.3389/fendo.2024.1403112 -
Cells Jul 2023Primary microcephalies (PMs) are defects in brain growth that are detectable at or before birth and are responsible for neurodevelopmental disorders. Most are caused by... (Review)
Review
Primary microcephalies (PMs) are defects in brain growth that are detectable at or before birth and are responsible for neurodevelopmental disorders. Most are caused by biallelic or, more rarely, dominant mutations in one of the likely hundreds of genes encoding PM proteins, i.e., ubiquitous centrosome or microtubule-associated proteins required for the division of neural progenitor cells in the embryonic brain. Here, we provide an overview of the different types of PMs, i.e., isolated PMs with or without malformations of cortical development and PMs associated with short stature (microcephalic dwarfism) or sensorineural disorders. We present an overview of the genetic, developmental, neurological, and cognitive aspects characterizing the most representative PMs. The analysis of phenotypic similarities and differences among patients has led scientists to elucidate the roles of these PM proteins in humans. Phenotypic similarities indicate possible redundant functions of a few of these proteins, such as ASPM and WDR62, which play roles only in determining brain size and structure. However, the protein pericentrin (PCNT) is equally required for determining brain and body size. Other PM proteins perform both functions, albeit to different degrees. Finally, by comparing phenotypes, we considered the interrelationships among these proteins.
Topics: Humans; Microcephaly; Centrosome; Brain; Brain Diseases; Body Size; Nerve Tissue Proteins; Cell Cycle Proteins
PubMed: 37443841
DOI: 10.3390/cells12131807 -
Best Practice & Research. Clinical... Dec 2023Growth hormone (GH) plays an essential role not only in promoting growth in children, but also in many important metabolic processes in adults. One of the major... (Review)
Review
Growth hormone (GH) plays an essential role not only in promoting growth in children, but also in many important metabolic processes in adults. One of the major metabolic functions of GH is its stimulatory effects on the liver in generating approximately 80% of circulating insulin-like growth factor 1 (IGF-1). Adult growth hormone deficiency (GHD) is an established clinical entity defined as a defect in endogenous GH secretion that is frequently associated with central obesity, loss of muscle mass, decreased bone mass, and impaired quality of life. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are conditions that are often under-recognized in adults with GHD, and accordingly some studies have shown that GH and IGF-1 levels are decreased in patients with NAFLD. Furthermore, it has been reported that it can progress to end-stage liver cirrhosis in some adults and children with GHD. Due to their underlying mechanisms of action, GH and IGF-1 can act on hepatocytes, macrophages, and hepatic stellate cells to mitigate progression to steatosis and fibrosis. It is, thus, important to recognize NAFLD/NASH as important complications in adult and childhood GHD. Therefore, careful and thorough evaluation of NAFLD/NASH in adults with GHD and the consideration for GH replacement therapy is crucial in these patients, together with management of other metabolic risk factors, such as obesity and dyslipidemia. This review will focus on recent reports on the role of GH and IGF-1 in the liver and its clinical significance in the regulation of hepatic function.
Topics: Adult; Child; Humans; Non-alcoholic Fatty Liver Disease; Insulin-Like Growth Factor I; Quality of Life; Growth Hormone; Human Growth Hormone; Dwarfism, Pituitary; Obesity
PubMed: 37643935
DOI: 10.1016/j.beem.2023.101816 -
Pediatric Clinics of North America Oct 2023Achondroplasia is the most common form of disproportionate severe short stature. Management of achondroplasia requires a multidisciplinary approach and has been largely... (Review)
Review
Achondroplasia is the most common form of disproportionate severe short stature. Management of achondroplasia requires a multidisciplinary approach and has been largely symptomatic for medical complications and psychosocial implications. Increased understanding of genetic and molecular mechanisms of achondroplasia has led to the development of novel disease-modifying drugs. The current drugs under investigation target the growth plate to stimulate chondrocyte growth and development. These include analogs of C-type natriuretic peptide (CNP), FGFR3-selective tyrosine kinase inhibitors, anti-FGFR3 antibodies, aptamers against FGF2, and soluble forms of FGFR3. Long-term data on the effects of these therapies on medical comorbidities are pending at this time.
Topics: Humans; Achondroplasia; Growth Disorders
PubMed: 37704353
DOI: 10.1016/j.pcl.2023.05.008