Riassunti dei progetti del corso di dottorato di ricerca in biologia molecolare e cellulare
Liu C, et al., Dev. Cell. 2009; 16 (5): 711-22
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- Cohen R, et al., Planta. 2009; 230(6): 1207-21.
- Location: Department of Biosciences, University of Milan, Italy
- Project leaders: PAOLO PLEVANI and GIACOMO BUSCEMI ( paolo.plevani@unimi.it ) ; (giacomo.buscemi@unimi.it)
Liu C, et al., Dev. Cell. 2009; 16 (5): 711-22.Jang S, et al., Plant J. 2009; 60: 614-25.Liu C, et al., Development 2007 134, 1901-1910.Gregis V, et al., The Plant J. 2009; 60: 626-37.Cohen R, et al.,Planta. 2009; 230(6): 1207-21.Berr A, et al., The Plant Cell. 2010; 22: 3232-48.Smaczniak C, et al., PNAS. 2012; 109: 1560-5 Project leader: KATIA PETRONI (katia.petroni@unimi.it)Location: Department of Biosciences, University of Milan, ItalyRESEARCH PROJECT SUMMARYRole of anthocyanin-enriched diet on cardioprotection Dietary flavonoids have received considerable attention since epidemiological studies have suggested that regular consumption of flavonoid-rich foods or beverages is associated with a decreased risk of cardiovascular mortality [1–3], attributed primarily to their antioxidant properties and by modulating cell signaling and metabolic pathways. Among the different classes of flavonoids, anthocyanins are the most recognized, visible members, that contribute to the cardioprotection. In these last years, recent studies have suggested that dietary flavonoids, and more specifically regular anthocyanin consumption, induce a state of myocardial resistance evidenced by a reduced infarct size following regional ischemia and reperfusion [4] that is related, at least in part, to an improvement in the antioxidant defenses of the heart (i.e. cardiac glutathione). Moreover, there are increasing evidences that seem to confirm that many biological effects of anthocyanins are related not only to their antioxidant properties but also to their ability to modulate mammalian cell signaling pathways. For instance, recent studies in rats have shown that an anthocyanin-rich diet modulate the metabolism of (n-3) PUFA and to induce a marked increase in plasma EPA and DHA, fatty acids known to be protective against heart disease complication [5,6]. Aim of this research proposal is to study the cardioprotective effects that an anthocyanin-enriched diet has on the myocardial muscle and also its role in the prevention of drug cardiotoxicity such as in the case of many antitumor drugs. With this aim, we will investigate as a dietary strategy whether using functional foods, as anthocyanin-rich corn, can have muscle protective properties and can reduce the incidence and prognosis of myopathies [6-7]. The project will be divided in three different tasks, including i) the role of dietary anthocyanins from corn in the prevention of cardiotoxicity induced by chemotherapic agents, ii), to investigate the effects of dietary anthocyanins on specific microRNAs involved in cardiac regeneration and aging, iii) to establish the molecular mechanism underpinning the cardioprotective action of anthocyanins in murine cardiomyocytes. With these activities, we expect to contribute to the understanding of how and why anthocyanins contribute to promote cardioprotection.
[1] Lancet 342:1007-11, 1993. [2] BMJ 312: 478-81, 1996 [3] Am J Clin Nutr 85:895-909, 2007. [4] FEBS J 273:2077-2099, 2006. [5] J Nutr 138:747-752, 2008. [6] J Nutr 141:37-41, 2011. [7] Lancet 374:1849-56, 2009. Project leaders: PAOLO PLEVANI and GIACOMO BUSCEMI (paolo.plevani@unimi.it); (giacomo.buscemi@unimi.it)Location: Department of Biosciences, University of Milan, ItalyRESEARCH PROJECT SUMMARYDAXX protein and the human DNA damage response: chromatin remodeling, gene expression, genome stability and tumorigenesis The DNA damage response (DDR) functions in cells to detect, signal and repair lesions to the nuclear DNA structure. The apical transducer of the DDR in human cells is the kinase ATM, which in response to double strand breaks (DSBs) phosphorylates a broad range of targets impacting on DNA repair, cell cycle arrest, senescence or apoptosis. ATM gene is mutated in ataxia telangiectasia, a rare disease characterized by neurological and immunological features and by cancer predisposition (1). Since DNA repair takes place within the complex organization of the chromatin, the DDR must be able to detect lesions within nucleosome-DNA template, remodel the local chromatin architecture for processing and repair lesions and restore the initial organization. DAXX is a chromatin-associated factor involved in transcriptional regulation working together with the DNA helicase ATRX, as a dedicated chaperone for the replication-independent deposition of the histone H3.3 variant onto gene regulatory regions as well as pericentric and telomeric heterochromatin (2). Mutations in DAXX, ATRX and H3.3 underlie paediatric/adult glioblastoma (3) and can associate in cancer with alternative lengthening of telomeres (ALT). Furthermore, DAXX interacts with several transcription factors, directly regulating gene expression. DAXX was initially linked to DNA damage for its role in p53 regulation and apoptosis (4), but the recent description of H3.3 deposition at UV damaged DNA sites by HIRA (5), an histones chaperone, suggest that DAXX histones chaperon activity could be involved in the DDR. Coherently, we have found that ATM and its mediator, Chk2, both phosphorylate DAXX on multiple residues, mutations of which impinge on DAXX activities, including DAXX/H3.3 interaction, suggesting that the ATM/Chk2/DAXX/H3.3 axis plays a role in chromatin dynamics in DDR, with potential implications for cancer pathogenesis. This project aims to provide a deep understanding of the molecular bases and functionality of DAXX in the cellular response to DNA DSBs. We will explore the hypothesis that DAXX could be targeted by DDR kinases redirecting its activity to modify chromatin and transcription at DNA damage sites and/or to modulate transcription of genes involved in DDR. This could occur through H3.3 deposition or directly through the functional interaction with specific transcription factors. Initially, we will determine how DAXX loss and expression of DAXX phospho-mutants affect genome stability, proliferation and survival after genotoxic stress. A specific role at telomeres or centromeres will also be assessed. Successively, we will evaluate if DAXX phosphorylations affect protein stability or localization and post-transcriptional modifications at other sites relevant for the activity of this protein. Finally, we will evaluate H3.3 deposition and chromatin modifications at DSBs or other genomic regions (i.e. telomeres). In the meantime human cell lines knock in for DAXX mutants will be produced to approach gene expression studies in presence of DNA damage. References: 1. Shiloh Y, Ziv Y. Nat Rev Mol Cell Biol. 2013 Apr;14(4):197-210. 2. Drané P, Ouararhni K, Depaux A, Shuaib M, Hamiche A. Genes Dev. 2010 Jun;24(12):1253-65. 3. Schwartzentruber J, et al., Nature. 2012 Jan 29;482(7384):226-31 4. Tang J, et al. Nat Cell Biol. 2006 Aug;8(8):855-62 5. Adam S, Polo SE, Almouzni G. Cell. 2013 Sep 26;155(1):94-106. Download 336.57 Kb. Share with your friends:
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