Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability

The genetic history of the Southern Arc: a bridge between West Asia and Europe

By sequencing 727 ancient individuals from the Southern Arc (Anatolia and its neighbors in Southeastern Europe and West Asia) over 10,000 years, we contextualize its Chalcolithic period and Bronze Age (about 5000 to 1000 BCE), when extensive gene flow entangled it with the Eurasian steppe. Two streams of migration transmitted Caucasus and Anatolian/Levantine ancestry northward, and the Yamnaya pastoralists, formed on the steppe, then spread southward into the Balkans and across the Caucasus into Armenia, where they left numerous patrilineal descendants. Anatolia was transformed by intra–West Asian gene flow, with negligible impact of the later Yamnaya migrations. This contrasts with all other regions where Indo-European languages were spoken, suggesting that the homeland of the Indo-Anatolian language family was in West Asia, with only secondary dispersals of non-Anatolian Indo-Europeans from the steppe

Effect of EU integration on media sector in Moldova

Almost two decades ago, just like other post-communist countries in Central and Eastern Europe, Republic of Moldova begun its transformation from the communist system to a liberal democracy and market economy. Again similarly to other courtiers in the region, Moldova set itself a goal to join EU. The process seemed irreversible even after the first victory, since Moldova proclaimed its independence in 1991, by the Moldova's Communist Party (PCRM) of the parliamentary elections in February 2001. Current thesis analyzed chances and some of the possible effects of the EU regulations in the field of media implementation in Moldova, where the old fashion Communist Party is in power for the last 8 years and in April 1009 succeeded to disputably win the general parliamentary elections for the third consecutive time. After ten years since Moldovan government announced European integration as a priority and the first official document framing the EU-Moldova relations was signed the real situation in the media sector did not improve much. There are objective reasons of this situation. Many European countries share the same characteristics such as historically strong party press, external rather internal pluralism, and strong state intervention. For post-communist countries in Central and Eastern Europe that tend to..

Investigation of the cytotoxic potential of methyl imidazole-derived thiosemicarbazones and their copper(II) complexes with dichloroacetate as a co-ligand

A series of six imidazole-derived thiosemicarbazones (HL1-HL6) and their copper(II) complexes (1-6) were synthesised and characterised by analytical, spectroscopic, electrochemical and single crystal X-ray diffraction techniques. In addition, solution studies and the results of antiproliferative activity in human cancer cell lines with some insights into the mechanism of cancer cell death are also reported. In particular, the substitution of one hydrogen at the terminal N-atom of the thiosemicarbazide moiety by a phenyl group resulted in slightly enhanced antiproliferative activity. HL3 and HL6 showed lower IC50 values compared to HL1 and HL4 in MDA-MB-453 and LS174 cancer cell lines. The copper(II) complexes 3 and 6 exhibit a 2.4- and 4.7-fold increase of activity compared to parent proligands in MDA-MB-453 cancer cell line, respectively. The complex formation of the proligands with copper(II) increased their antiproliferative activity in all investigated cell lines. The cell cycle perturbations, apoptotic potential and the analysis of morphological changes in the A549 cell line induced by 3 and 6 revealed cytostatic rather than cytotoxic effects

Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H2LR]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HLR)Cl]Cl (1–4) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1–3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: 3 > 2 > 4 > cisplatin > 1 >> [H2LR]Cl. The copper(II) complexes showed marked interaction with OCT1–3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors