DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of lamin A/C.

The integrity of the nuclear envelope (NE) is essential for maintaining the structural stability of the nucleus. Rupture of the NE has been frequently observed in cancer cells, especially in the context of mechanical challenges, such as physical confinement and migration. However, spontaneous NE rupture events, without any obvious physical challenges to the cell, have also been described. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation leads to NE rupture. Upon DNA damage, lamin A/C is phosphorylated in an ATR-dependent manner, leading to changes in lamina assembly and, ultimately, NE rupture. In addition, we show that cancer cells with intrinsic DNA repair defects undergo frequent events of DNA-damage-induced NE rupture, which renders them extremely sensitive to further NE perturbations. Exploiting this NE vulnerability could provide a new angle to complement traditional, DNA-damage-based chemotherapy.

Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis.

DNA double-strand breaks (DSBs) are deleterious lesions that challenge genome integrity. To mitigate this threat, human cells rely on the activity of multiple DNA repair machineries that are tightly regulated throughout the cell cycle1. In interphase, DSBs are mainly repaired by non-homologous end joining and homologous recombination2. However, these pathways are completely inhibited in mitosis3-5, leaving the fate of mitotic DSBs unknown. Here we show that DNA polymerase theta6 (Polθ) repairs mitotic DSBs and thereby maintains genome integrity. In contrast to other DSB repair factors, Polθ function is activated in mitosis upon phosphorylation by Polo-like kinase 1 (PLK1). Phosphorylated Polθ is recruited by a direct interaction with the BRCA1 C-terminal domains of TOPBP1 to mitotic DSBs, where it mediates joining of broken DNA ends. Loss of Polθ leads to defective repair of mitotic DSBs, resulting in a loss of genome integrity. This is further exacerbated in cells that are deficient in homologous recombination, where loss of mitotic DSB repair by Polθ results in cell death. Our results identify mitotic DSB repair as the underlying cause of synthetic lethality between Polθ and homologous recombination. Together, our findings reveal the critical importance of mitotic DSB repair in the maintenance of genome integrity.

Parallel palaeogenomic transects reveal complex genetic history of early European farmers.

Ancient DNA studies have established that Neolithic European populations were descended from Anatolian migrants who received a limited amount of admixture from resident hunter-gatherers. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Here we investigate the population dynamics of Neolithization across Europe using a high-resolution genome-wide ancient DNA dataset with a total of 180 samples, of which 130 are newly reported here, from the Neolithic and Chalcolithic periods of Hungary (6000-2900 bc, n = 100), Germany (5500-3000 bc, n = 42) and Spain (5500-2200 bc, n = 38). We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways in which gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modelling approaches to elucidate multiple dimensions of historical population interactions.

Tracing the genetic origin of Europe's first farmers reveals insights into their social organization.

Farming was established in Central Europe by the Linearbandkeramik culture (LBK), a well-investigated archaeological horizon, which emerged in the Carpathian Basin, in today's Hungary. However, the genetic background of the LBK genesis is yet unclear. Here we present 9 Y chromosomal and 84 mitochondrial DNA profiles from Mesolithic, Neolithic Starcevo and LBK sites (seventh/sixth millennia BC) from the Carpathian Basin and southeastern Europe. We detect genetic continuity of both maternal and paternal elements during the initial spread of agriculture, and confirm the substantial genetic impact of early southeastern European and Carpathian Basin farming cultures on Central European populations of the sixth-fourth millennia BC. Comprehensive Y chromosomal and mitochondrial DNA population genetic analyses demonstrate a clear affinity of the early farmers to the modern Near East and Caucasus, tracing the expansion from that region through southeastern Europe and the Carpathian Basin into Central Europe. However, our results also reveal contrasting patterns for male and female genetic diversity in the European Neolithic, suggesting a system of patrilineal descent and patrilocal residential rules among the early farmers.

Virulence Spectra of Hungarian Pyrenophora teres f. teres Isolates Collected from Experimental Fields Show Continuous Variation without Specific Isolate × Barley Differential Interactions.

Pyrenophora teres f. teres (Ptt), the causal agent of net form net blotch (NFNB) disease, is an important and widespread pathogen of barley. This study aimed to quantify and characterize the virulence of Ptt isolates collected from experimental fields of barley in Hungary. Infection responses across 20 barley differentials were obtained from seedling assays of 34 Ptt isolates collected from three Hungarian breeding stations between 2008 and 2018. Twenty-eight Ptt pathotypes were identified. Correspondence analysis followed by hierarchical clustering on the principal components and host-by-pathogen GGE biplots suggested a continuous range of virulence and an absence of specific isolate × barley differential interactions. The isolates were classified into four isolate groups (IG) using agglomerative hierarchical clustering. One IG could be distinguished from other IGs based on avirulence/virulence on one to five barley differentials. Several barley differentials expressed strong resistance against multiple Ptt isolates and may be useful in the development of NFNB-resistant barley cultivars in Hungary. Our results emphasize that the previously developed international barley differential set needs to be improved and adapted to the Hungarian Ptt population. This is the first report on the pathogenic variations of Ptt in Hungary.

Possible cases of leprosy from the Late Copper Age (3780-3650 cal BC) in Hungary.

At the Abony-Turjányos dulo site, located in Central Hungary, a rescue excavation was carried out. More than 400 features were excavated and dated to the Protoboleráz horizon, at the beginning of the Late Copper Age in the Carpathian Basin, between 3780-3650 cal BC. Besides the domestic and economic units, there were two special areas, with nine-nine pits that differed from the other archaeological features of the site. In the northern pit group seven pits contained human remains belonging to 48 individuals. Some of them were buried carefully, while others were thrown into the pits. The aim of this study is to present the results of the paleopathological and molecular analysis of human remains from this Late Copper Age site. The ratio of neonates to adults was high, 33.3%. Examination of the skeletons revealed a large number of pathological cases, enabling reconstruction of the health profile of the buried individuals. Based on the appearance and frequency of healed ante- and peri mortem trauma, inter-personal (intra-group) violence was characteristic in the Abony Late Copper Age population. However other traces of paleopathology were observed on the bones that appear not to have been caused by warfare or inter-group violence. The remains of one individual demonstrated a rare set of bone lesions that indicate the possible presence of leprosy (Hansen's disease). The most characteristic lesions occurred on the bones of the face, including erosion of the nasal aperture, atrophy of the anterior nasal spine, inflammation of the nasal bone and porosity on both the maxilla and the bones of the lower legs. In a further four cases, leprosy infection is suspected but other infections cannot be excluded. The morphologically diagnosed possible leprosy case significantly modifies our knowledge about the timescale and geographic spread of this specific infectious disease. However, it is not possible to determine the potential connections between the cases of possible leprosy and the special burial circumstances.