Induction of \u3cem\u3eIL19\u3c/em\u3e Expression through JNK and cGAS-STING Modulates DNA Damage–Induced Cytokine Production

Cytokine production is a critical component of cell-extrinsic responses to DNA damage and cellular senescence. Here, we demonstrated that expression of the gene encoding interleukin-19 (IL-19) was enhanced by DNA damage through pathways mediated by c-Jun amino-terminal kinase (JNK) and cGAS-STING and that IL19 expression was required for the subsequent production of the cytokines IL-1, IL-6, and IL-8. IL19 expression was stimulated by diverse cellular stresses, including inhibition of the DNA replication checkpoint kinase ATR (ataxia telangiectasia and Rad3-related protein), oncogene expression, replicative exhaustion, oxidative stress, and DNA double-strand breaks. Unlike the production of IL-6 and IL-8, IL19 expression was not affected by abrogation of signaling by the IL-1 receptor (IL-1R) or the mitogen-activated protein kinase p38. Instead, the DNA damage–induced production of IL-1, IL-6, and IL-8 was substantially reduced by suppression of IL19 expression. The signaling pathways required to stimulate IL19 expression selectively depended on the type of DNA-damaging agent. Reactive oxygen species and the ASK1-JNK pathway were critical for responses to ionizing radiation (IR), whereas the cGAS-STING pathway stimulated IL19 expression in response to either IR or ATR inhibition. Whereas induction of IL1, IL6, and IL8 by IR depended on IL19 expression, the cGAS-STING–dependent induction of the immune checkpoint gene PDL1 after IR and ATR inhibition was independent of IL19. Together, these results suggest that IL-19 production by diverse pathways forms a distinct cytokine regulatory arm of the response to DNA damage

Replicative stress, stem cells and aging

Cilj ovog rada je analizirati mogućnosti razvoja specifičnih oblika turizma kao mjeru održivog razvoja turizma na području Europske unije. Europa kao vodeća turistička regija svijeta ima dobre temelje i tradiciju turizma te u skladu s time i olakšane mogućnosti daljnjeg razvoja raznih oblika turizma. U radu se analizira razvoj turističke politike EU te posebno mjere i aktivnosti usmjerene u cilju održivog razvoja turizma. Poseban osvrt se daje na mogućnosti razvoja pojedinih specifičnih oblika turizma kao što su ekoturizam, sportsko-rekreacijski turizam s posebnim osvrtom na cikloturizam, zatim omladinski turizam, kulturni turizam, enogastronomski te ukratko na ostale specifične oblike turizma u odabranim zemljama članicama EU s posebnim osvrtom na Republiku Hrvatsku. U radu su korišteni sekundarni izvori podataka pri čemu je proučena relevantna znanstvena i stručna literatura te razni internetski izvori o temi istraživanja.The purpose of this graduate thesis is to analyze the possibilites of special interest tourism development as a measure of sustainable tourism development in the European Union and in Republic of Croatia. Europe is the leading tourism region of the world; it has its background and tradition of tourism and facilitated possibilities od further development of numerous forms of tourism. The dissertation analyzes development of tourism policy of the EU, particularly measures and activities aimed at the sustainable development of tourism. Special attention is given to the development of ecotourism, sports and recreational tourism with emphasis on cyclotourism, youth tourism, cultural tourism, enogastronomic tourism and, shortly, on other special interest tourism in selected EU member states with emphasis on the Republic of Croatia. The dissertation is based on secondary sources that were studied with all the relevant professional and scientific literature on the topic of research; also numerous online sources have been studied in addition to those sources

ATR acts stage specifically to regulate multiple aspects of mammalian meiotic silencing

In mammals, homologs that fail to synapse during meiosis are transcriptionally inactivated. This process, meiotic silencing, drives inactivation of the heterologous XY bivalent in male germ cells (meiotic sex chromosome inactivation [MSCI]) and is thought to act as a meiotic surveillance mechanism. The checkpoint protein ATM and Rad3-related (ATR) localizes to unsynapsed chromosomes, but its role in the initiation and maintenance of meiotic silencing is unknown. Here we show that ATR has multiple roles in silencing. ATR first regulates HORMA (Hop1, Rev7, and Mad2) domain protein HORMAD1/2 phosphorylation and localization of breast cancer I (BRCA1) and ATR cofactors ATR-interacting peptide (ATRIP)/topoisomerase 2-binding protein 1 (TOPBP1) at unsynapsed axes. Later, it acts as an adaptor, transducing signaling at unsynapsed axes into surrounding chromatin in a manner that requires interdependence with mediator of DNA damage checkpoint 1 (MDC1) and H2AFX. Finally, ATR catalyzes histone H2AFX phosphorylation, the epigenetic event leading to gene inactivation. Using a novel genetic strategy in which MSCI is used to silence a chosen gene in pachytene, we show that ATR depletion does not disrupt the maintenance of silencing and that silencing comprises two phases: The first is dynamic and reversible, and the second is stable and irreversible. Our work identifies a role for ATR in the epigenetic regulation of gene expression and presents a new technique for ablating gene function in the germlin