DNA damage response Dotaz Zobrazit nápovědu
Důležitou úlohou oocytů je zajištění přenosu genetické informace do dalších generací. Narušení integrity DNA oocytů může představovat riziko pro zrání oocytů a vývoj embrya, a aktivní mechanizmy detekce a opravy poškozené DNA jsou proto nezbytné pro přežití potomstva. Nejnovější studie však ukazují, že oocyty jsou schopné zrát i za přítomností poškozené DNA až do embryonálního stádia a reagují pouze na větší míru poškození. Nicméně oocyty mají kapacitu průběžně opravovat DNA během zrání, otázkou však zůstává efektivita této opravy.
An important role of oocytes is transmission of genetic information to the next generations. Disruption of DNA integrity may affect maturation of oocytes and embryo development and active mechanisms of DNA damage detection and repair are thus needed for the successful reproduction. However, the recent studies show that oocytes are able to mature in the presence of damaged DNA until the embryonic stage and respond only to higher levels of damage. Nevertheless, the oocytes have the capacity to repair DNA throughout meiotic maturation, however the effectivity of the process remains unclear.
- MeSH
- embryonální vývoj MeSH
- lidé MeSH
- modely u zvířat MeSH
- myši MeSH
- oocyty * MeSH
- oprava DNA MeSH
- poškození DNA * MeSH
- výzkum embrya MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
XIV, 411 s. : il.
The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.
DNA damage response (DDR) emerges as a biological tumorigenesis barrier in early stages of cancer development, and a selective pressure that favors outgrowth of malignant clones with defects in the genome maintenance machinery, such as mutations of p53 and other DDR components. Recent studies indicate that the DDR barrier is not alarmed universally among early noninvasive lesions, but rather responds to high-risk tumorigenic threats that occur in high-grade, pre-malignant lesions that are generally more likely to develop into bona fide malignancies. In addition, while the DDR barrier appears to operate in major types of cancer, such as carcinomas of the lung, breast and colon, DDR activation is rare at any stage of progression among testicular germ-cell tumors. Together with observations that several, but not all oncogenic insults are capable of activating the DDR machinery, these new results point to existence of a critical threshold of such oncogene-induced DNA damage. It seems that only cells and lesions that experience DNA replication stress and DNA damage above such threshold activate the cellular senescence or cell death pathways within the DDR machinery. The higher load of DNA damage may also contribute to cancer predisposition in families with inherited heterozygous defects in the DDR barrier, such as in ATM, BRCA1, BRCA2, p53 and other genes. We propose that carriers of such DDR defects may be more prone to malignancy due to 'conditional haploinsufficiency': such partial defects may be asymptomatic in normal tissues, yet they may become manifest under conditions of supra-threshold endogenous DNA damage in oncogene-driven pre-malignant lesions.
sv.
BACKGROUND: The ATM kinase constitutes a master regulatory hub of DNA damage and activates the p53 response pathway by phosphorylating the MDM2 protein, which develops an affinity for the p53 mRNA secondary structure. Disruption of this interaction prevents the activation of the nascent p53. The link of the MDM2 protein-p53 mRNA interaction with the upstream DNA damage sensor ATM kinase and the role of the p53 mRNA in the DNA damage sensing mechanism, are still highly anticipated. METHODS: The proximity ligation assay (PLA) has been extensively used to reveal the sub-cellular localisation of the protein-mRNA and protein-protein interactions. ELISA and co-immunoprecipitation confirmed the interactions in vitro and in cells. RESULTS: This study provides a novel mechanism whereby the p53 mRNA interacts with the ATM kinase enzyme and shows that the L22L synonymous mutant, known to alter the secondary structure of the p53 mRNA, prevents the interaction. The relevant mechanistic roles in the DNA Damage Sensing pathway, which is linked to downstream DNA damage response, are explored. Following DNA damage (double-stranded DNA breaks activating ATM), activated MDMX protein competes the ATM-p53 mRNA interaction and prevents the association of the p53 mRNA with NBS1 (MRN complex). These data also reveal the binding domains and the phosphorylation events on ATM that regulate the interaction and the trafficking of the complex to the cytoplasm. CONCLUSION: The presented model shows a novel interaction of ATM with the p53 mRNA and describes the link between DNA Damage Sensing with the downstream p53 activation pathways; supporting the rising functional implications of synonymous mutations altering secondary mRNA structures.
Human cells are subjected to continuous challenges by different genotoxic stress attacks. DNA damage leads to erroneous mutations, which can alter the function of oncogenes or tumor suppressors, resulting in cancer development. To circumvent this, cells activate the DNA damage response (DDR), which mainly involves cell cycle regulation and DNA repair processes. The tumor suppressor p53 plays a pivotal role in the DDR by halting the cell cycle and facilitating the DNA repair processes. Various pathways and factors participating in the detection and repair of DNA have been described, including scores of RNA-binding proteins (RBPs) and RNAs. It has become increasingly clear that p53's role is multitasking, and p53 mRNA regulation plays a prominent part in the DDR. This review is aimed at covering the p53 RNA metabolism linked to the DDR and highlights the recent findings.
- MeSH
- lidé MeSH
- messenger RNA metabolismus MeSH
- mutace MeSH
- nádorový supresorový protein p53 genetika metabolismus MeSH
- nepřekládané oblasti MeSH
- oprava DNA * fyziologie MeSH
- poškození DNA * MeSH
- proteiny vázající RNA genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Ataxia-telangiectasia mutated kinase (ATM) is a DNA damage-inducible protein kinase, which phosphorylates plethora of substrates participating in DNA damage response. ATM significance for the cell faith is undeniable, since it regulates DNA repair, cell-cycle progress, and apoptosis. Here we describe its main signalling targets and discuss its importance in DNA repair as well as novel findings linked to this key regulatory enzyme in the terms of ionizing radiationinduced DNA damage.
