1,720,999 research outputs found
Targeting DNA damage response: threshold, chromatin landscape and beyond
Full text linkCells are continually exposed to DNA assaults from exogenous and endogenous sources. To maintain genomic integrity, cells have evolved a highly conserved mechanism for repairing DNA lesions and, in particular, DNA double strand breaks (DSBs). Emerging evidence indicates that DNA repair/signaling machinery acts in an integrated fashion with chromatin structure at damaged sites. This review focuses on the interplay between histone modifications and the chromatin-mediated response to DNA damage
DNA damage stress response in germ cells: role of c-Abl and clinical implications
No full textCells experiencing DNA damage undergo a complex response entailing cell-cycle arrest, DNA repair and apoptosis, the relative importance of the three being modulated by the extent of the lesion. The observation that Abl interacts in the nucleus with several proteins involved in different aspects of DNA repair has led to the hypothesis that this kinase is part of the damage-sensing mechanism. However, the mechanistic details underlying the role of Abl in DNA repair remain unclear. Here, I will review the evidence supporting our current understanding of Abl activation following DNA insults, while focusing on the relevance of these mechanisms in protecting DNA-injured germ cells. Early studies have shown that Abl transcripts are highly expressed in the germ line. Abl-deficient mice exhibit multiple abnormalities, increased perinatal mortality and reduced fertility. Recent findings have implicated Abl in a cisplatin-induced signaling pathway eliciting death of immature oocytes. A p53-related protein, TAp63, is an important immediate downstream effector of this pathway. Of note, pharmacological inhibition of Abl protects the ovarian reserve from the toxic effects of cisplatin. This suggests that the extent of Abl catalytic outputs may shift the balance between survival (likely through DNA repair) and activation of a death response. Taken together, these observations are consistent with the evolutionary conserved relationship between DNA damage and activation of the p53 family of transcription factors, while shedding light on the key role of Abl in dictating the fate of germ cells upon genotoxic insults
Defying c-Abl signaling circuits through small allosteric compounds
No full textMany extracellular and intracellular signals promote the c-Abl tyrosine kinase activity. c-Abl in turn triggers a multitude of changes either in protein phosphorylation or in gene expression in the cell. Yet, c-Abl takes part in diverse signaling routes because of several domains linked to its catalytic core. Complex conformational changes turn on and off its kinase activity. These changes affect surface features of the c-Abl kinase and likely its capability to bind actin and/or DNA. Two specific inhibitors (ATP-competitive or allosteric compounds) regulate the c-Abl kinase through different mechanisms. NMR studies show that a c-Abl fragment (SH3-SH2-linker-SH1) adopts different conformational states upon binding to each inhibitor. This supports an unconventional use for allosteric compounds to unraveling physiological c-Abl signaling circuits
Asciminib mitigates DNA damage stress signaling induced by cyclophosphamide in the ovary
Full text linkCancer treatments often have adverse effects on the quality of life for young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signalling pathways activated by cyclophosphamide in mouse ovaries. Besides, we provide evidence that Asciminib did not interfere with the cytotoxic effect of cyclophosphamide in MCF7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without preventing the anticancer potential of cyclophosphamide. Altogether these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effect of cancer therapies
DNA damage response: the emerging role of c-Abl as a regulatory switch?
Full text linkA complex regulatory network of signaling pathways safeguards genome integrity following DNA damage. When double strand breaks occur several enzymes and mediators are recruited to the sites of lesion to release a network of DNA repair processes referred to as DNA damage response (DDR). c-Abl interacts in the nucleus with several proteins implicated in distinct aspects of DNA repair. This suggests that c-Abl may be involved in the regulation of double strand break repair. The involvement of c-Abl in DNA repair mechanisms came into the spotlight in female germ cells under genotoxic stress. Recent findings have implicated c-Abl in a cisplatin-induced signaling pathway eliciting death of immature oocytes. Pharmacological inhibition of c-Abl by Imatinib (STI571) protects the ovarian reserve from the toxic effect of cisplatin. This implies that the extent of c-Abl catalytic outcomes may tip the balance between survival (likely through DNA repair) and activation of a death response. Many observations indicate that timely ubiquitin-modifications and signal decoding are implicated in regulating DNA repair. Here, we discuss some connections between phosphorylation- and ubiquitin-mediated signaling at the damaged sites. We speculate about multiple interactions that may occur between c-Abl (and 'sensor' kinases) with ubiquitin-related proteins involved in DDR. Additional work is required to understand the complexity of the physiological outcomes of c-Abl in DDR. However, a fine-tuning of nuclear outcomes, through pharmacological inhibition of c-Abl, may provide novel paradigms for DDR and, potentially, therapeutic strategies for cancer treatmen
P63 in health and cancer
Full text linkTP63 is the most ancient member of the p53 gene family. The p53 family comprises three transcription factors (p53/p63/p73). They share a high degree of homology and similar domain structure. Yet, they can exist as truncated isoforms. Alternative promoters and splicing sites lead to the generation of several molecules. P53/p63/p73 are important to maintain cell homeostasis. P63 and p73 regulate many p53 target genes. This is due to their common structural features. Both proteins may compensate the loss of p53. This is a common event occurring in more than 50% of malignancies. Yet, p63 (or p73) has its own role. Studies from p63-null mice have shown the key role of p63 in embryo development. Several reports have supported the p63 role in epidermal development and in skin homeostasis. P63 involvement in heart development is currently being researched. Recent studies have found p63 to be "the guardian of human reproduction". In addition, p63 has an important, even controversial, role in cancer. Here, we provide a general overview of p63 regulation and activity. We discuss emerging concepts about its role in germ line protection, metabolism and cancer
Dissecting NGF interactions with TrkA and p75 receptors by structural and functional studies of an anti-NGF neutralizing antibody
No full textThe anti-nerve growth factor (NGF) monoclonal antibody alphaD11 is a potent antagonist that neutralizes the biological functions of its antigen in vivo. NGF antagonism is expected to be a highly effective and safe therapeutic approach in many pain states. A comprehensive functional and structural analysis of alphaD11 monoclonal antibody was carried out, showing its ability to neutralize NGF binding to either tropomyosine receptor kinase A (TrkA) or p75 receptors. The 3-D structure of the alphaD11 Fab fragment was solved at 1.7 A resolution. A computational docking model of the alphaD11 Fab-NGF complex, based on epitope mapping using a pool of 44 NGF mutants and experimentally validated by small-angle X-ray scattering, provided the structural basis for identifying the residues involved in alphaD11 Fab binding. The present study pinpoints loop II of NGF to be an important structural determinant for NGF biological activity mediated by TrkA receptor
The effects of anti-nerve growth factor monoclonal antibodies on developing basal forebrain neurons are transient and reversible
No full textIn order to reassess the role of nerve growth factor (NGF) on rat basal forebrain cholinergic neurons (BFCNs) survival and/or phenotype maturation during the early postnatal life, we immunoneutralized NGF in vivo. Hybridoma cells producing the neutralizing anti-NGF monoclonal antibody alpha D11 were implanted in the lateral ventricle of the rat at different postnatal ages (P2, P8 and P15) and the effects on the number and the soma size of cholinacetyltransferase (ChAT) positive neurons were analysed 1, 2 or 3 weeks after the injection. A marked decrease in the number and in the soma size of BFCNs was observed implanting hybridoma cells at P2 and performing the analysis 1 week later. These effects are reversed 3 weeks after the implant of hybridoma cells at P2. At this time point, the levels of alpha D11 antibodies in the brain parenchyma are still in a vast molar excess over endogenous NGF, No effects on BFCNs were observed implanting alpha D11 cells at P15 while LGN neurons showed marked shrinkage. Our results demonstrate that the reduction in the number of ChAT-positive neurons during the first two postnatal weeks of anti-NGF treatment is not due to cell death. We conclude that NGF is not a survival factor for BFCNs, and that the influence of NGF on BFCNs cell maturation during the first 2 postnatal weeks is transient and reversible. Our results on tyrosine kinase (Trk) coexpression, suggest that NGF may cooperate with other factors in the cholinergic phenotype differentiation and maintenance after the second postnatal week
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