Spatially organized multicellular immune hubs in human colorectal cancer

1. Download : Download high-res image (274KB)
2. Download : Download full-size image

     

Structural Insights into the Mechanism of Base Excision by MBD4

DNA glycosylases remove damaged or modified nucleobases by cleaving the N-glycosyl bond and the correct nucleotide is restored through subsequent base excision repair. In addition to excising threatening lesions, DNA glycosylases contribute to epigenetic regulation by mediating DNA demethylation and perform other important functions. However, the catalytic mechanism remains poorly defined for many glycosylases, including MBD4 (methyl-CpG binding domain IV), a member of the helix-hairpin-helix (HhH) superfamily. MBD4 excises thymine from G·T mispairs, suppressing mutations caused by deamination of 5-methylcytosine, and it removes uracil and modified uracils (e.g., 5-hydroxymethyluracil) mispaired with guanine. To investigate the mechanism of MBD4 we solved high-resolution structures of enzyme-DNA complexes at three stages of catalysis. Using a non-cleavable substrate analog, 2′-deoxy-pseudouridine, we determined the first structure of an enzyme-substrate complex for wild-type MBD4, which confirms interactions that mediate lesion recognition and suggests that a catalytic Asp, highly conserved in HhH enzymes, binds the putative nucleophilic water molecule and stabilizes the transition state. Observation that mutating the Asp (to Gly) reduces activity by 2700-fold indicates an important role in catalysis, but probably not one as the nucleophile in a double-displacement reaction, as previously suggested. Consistent with direct-displacement hydrolysis, a structure of the enzyme-product complex indicates a reaction leading to inversion of configuration. A structure with DNA containing 1-azadeoxyribose models a potential oxacarbenium-ion intermediate and suggests the Asp could facilitate migration of the electrophile towards the nucleophilic water. Finally, the structures provide detailed snapshots of the HhH motif, informing how these ubiquitous metal-binding elements mediate DNA binding.     

Function and underlying mechanisms of seasonal colour moulting in mammals and birds: what keeps them changing in a warming world?

Animals that occupy temperate and polar regions have specialized traits that help them survive in harsh, highly seasonal environments. One particularly important adaptation is seasonal coat colour (SCC) moulting. Over 20 species of birds and mammals distributed across the northern hemisphere undergo complete, biannual colour change from brown in the summer to completely white in the winter. But as climate change decreases duration of snow cover, seasonally winter white species (including the snowshoe hare Lepus americanus, Arctic fox Vulpes lagopus and willow ptarmigan Lagopus lagopus) become highly contrasted against dark snowless backgrounds. The negative consequences of camouflage mismatch and adaptive potential is of high interest for conservation. Here we provide the first comprehensive review across birds and mammals of the adaptive value and mechanisms underpinning SCC moulting. We found that across species, the main function of SCC moults is seasonal camouflage against snow, and photoperiod is the main driver of the moult phenology. Next, although many underlying mechanisms remain unclear, mammalian species share similarities in some aspects of hair growth, neuroendocrine control, and the effects of intrinsic and extrinsic factors on moult phenology. The underlying basis of SCC moults in birds is less understood and differs from mammals in several aspects. Lastly, our synthesis suggests that due to limited plasticity in SCC moulting, evolutionary adaptation will be necessary to mediate future camouflage mismatch and a detailed understanding of the SCC moulting will be needed to manage populations effectively under climate change.     

Optimal reproductive phenology under size‐dependent cannibalism

Intra‐cohort cannibalism is an example of a size‐mediated priority effect. If early life stages cannibalize slightly smaller individuals, then parents face a trade‐off between breeding at the best time for larval growth or development and predation risk from offspring born earlier. This game‐theoretic situation among parents may drive adaptive reproductive phenology toward earlier breeding. However, it is not straightforward to quantify how cannibalism affects seasonal egg fitness or to distinguish emergent breeding phenology from alternative adaptive drivers. Here, we devise an age‐structured game‐theoretic mathematical model to find evolutionary stable breeding phenologies. We predict how size‐dependent cannibalism acting on eggs, larvae, or both changes emergent breeding phenology and find that breeding under inter‐cohort cannibalism occurs earlier than the optimal match to environmental conditions. We show that emergent breeding phenology patterns at the level of the population are sensitive to the ontogeny of cannibalism, that is, which life stage is subject to cannibalism. This suggests that the nature of cannibalism among early life stages is a potential driver of the diversity of reproductive phenologies seen across taxa and may be a contributing factor in situations where breeding occurs earlier than expected from environmental conditions.     

Atlas versus range maps: robustness of chorological relationships to distribution data types in European mammals

Aim Chorological relationships describe the patterns of distributional overlap among species. In addition to revealing biogeographical structure, the resulting clusters of species with similar geographical distributions can serve as natural units in conservation planning. Here, we assess the extent to which temporal, methodological and taxonomical differences in the source of species’ distribution data can affect the relationships that are found. Location Western Europe. Methods We used two data sets – the Atlas of European mammals and polygon range maps from the IUCN Global Mammal Assessment – both as presence–absence data for UTM 50 km × 50 km squares. We performed pairwise comparisons among 156 species for each data set to build matrices of the similarity in distribution across species, using both Jaccard’s and Baroni‐Urbani & Buser’s indices. We then compared these similarity matrices (chorological relationships), as well as the species richness and occurrence patterns from the two data sets. Results As expected, range maps increased both the mean prevalence per species and mean species richness per grid cell in comparison to atlas data, reflecting the general view that these data types respectively over‐ and underestimate species occurrence. However, species richness and occurrence patterns in atlas and range map data were positively associated and, most importantly, the chorological relationships underlying the two data sets were highly similar. Main conclusions Despite many methodological, temporal and taxonomical differences between atlas data and range maps, the chorological relationships encountered between species were similar for both data sets. Chorological analyses can thus be robust to the data source used and provide a solid basis for analytical biogeographical studies, even over broad spatial scales.     

Timing and abundance as key mechanisms affecting trophic interactions in variable environments

Climatic changes are disrupting otherwise tight trophic interactions between predator and prey. Most of the earlier studies have primarily focused on the temporal dimension of the relationship in the framework of the match–mismatch hypothesis. This hypothesis predicts that predator's recruitment will be high if the peak of the prey availability temporally matches the most energy‐demanding period of the predators breeding phenology. However, the match–mismatch hypothesis ignores the level of food abundance while this can compensate small mismatches. Using a novel time‐series model explicitly quantifying both the timing and the abundance component for trophic relationships, we here show that timing and abundance of food affect recruitment differently in a marine (cod/zooplankton), a marine–terrestrial (puffin/herring) and a terrestrial (sheep/vegetation) ecosystem. The quantification of the combined effect of abundance and timing of prey on predator dynamics enables us to come closer to the mechanisms by which environment variability may affect ecological systems.     

Low-Molecular-Weight DNA Replication Intermediates in Escherichia coli: Mechanism of Formation and Strand Specificity

Chromosomal DNA replication intermediates, revealed in ligase-deficient conditions in vivo, are of low molecular weight (LMW) independently of the organism, suggesting discontinuous replication of both the leading and the lagging DNA strands. Yet, in vitro experiments with purified enzymes replicating sigma-structured substrates show continuous synthesis of the leading DNA strand in complete absence of ligase, supporting the textbook model of semi-discontinuous DNA replication. The discrepancy between the in vivo and in vitro results is rationalized by proposing that various excision repair events nick continuously synthesized leading strands after synthesis, producing the observed LMW intermediates. Here, we show that, in an Escherichia coli ligase-deficient strain with all known excision repair pathways inactivated, new DNA is still synthesized discontinuously. Furthermore, hybridization to strand-specific targets demonstrates that the LMW replication intermediates come from both the lagging and the leading strands. These results support the model of discontinuous leading strand synthesis in E. coli.     

Protein–lipid interactions studied with designed transmembrane peptides: role of hydrophobic matching and interfacial anchoring (Review)

Biological membranes are characterized by a heterogeneous composition, which is not only manifested in the wide variety of their components, but also in aspects like the lateral organization, topology, and conformation of proteins and lipids. In bringing about the correct membrane structure, protein–lipid interactions can be expected to play a prominent role. The extent of hydrophobic matching between transmembrane protein segments and lipids potentially constitutes a versatile director of membrane organization, because a tendency to avoid hydrophobic mismatch could result in compensating adaptations such as tilt of the transmembrane segment or segregation into distinct domains. Also, interfacial interactions between lipid headgroups and the aromatic and charged residues that typically flank transmembrane domains may act as an organizing element. In this review, we discuss the numerous model studies that have systematically explored the influence of hydrophobic matching and interfacial anchoring on membrane structure. Designed peptides consisting of a polyleucine or polyleucine/alanine hydrophobic stretch, which is flanked on both sides by tryptophan or lysine residues, reflect the general layout of transmembrane protein segments. It is shown for phosphatidylcholine bilayers and for other model membranes that these peptides adapt a transmembrane topology without extensive peptide or lipid adaptations under conditions of hydrophobic matching, but that significant rearrangements can result from hydrophobic mismatch. Moreover, these effects depend on the nature of the flanking residues, implying a modulation of the mismatch response by interfacial interactions of the flanking residues. The implications of these model studies for the organization of biomembranes are discussed in the context of recent experiments with more complex systems.     

Novel PTEN germline mutation in a family with mild phenotype: Difficulties in genetic counseling

PTEN gene (phosphatase and tensin homolog deleted on chromosome ten, MIM 601628) is a tumor suppressor gene implicated in PTEN hamartoma tumor syndromes (PHTS) including Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome and Proteus-like syndrome. PTEN mutations have been more recently reported in children with macrocephaly and autism spectrum disorders or mental retardation, without other symptoms of PHTS. Although tumor risk has not been evaluated in these patients and their relatives, the same surveillance as for Cowden syndrome is usually proposed. We report a family including patients carrying a novel PTEN mutation and presenting with a mild phenotype consisting of macrocephaly, hypotonia during the first year of life and mild learning disabilities, without autistic features. None of these patients exhibited PTHS-related symptoms such as tumors, lipomas, vascular malformations or pigmented macules of the glans penis. This report raises the question of extending the indications of PTEN mutation screening to familial macrocephaly with learning disabilities. Detection of a mutation in this family led to difficult questions about surveillance, genetic counseling and familial information since the mother declined tumor screening and disclosure of genetic risk information to at-risk relatives.     

Association between the XRCC3 T241M polymorphism and risk of cancer: Evidence from 157 case–control studies

The T241M polymorphism in the X-ray cross-complementing group 3 (XRCC3) had been implicated in cancer susceptibility. The previous published data on the association between XRCC3 T241M polymorphism and cancer risk remained controversial. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and XRCC3 T241M (61,861 cases and 84,584 controls from 157 studies) polymorphism in different inheritance models. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ration [OR] = 1.07, 95% confidence interval [CI] = 1.00–1.13; recessive model: OR = 1.15, 95% CI = 1.08–1.23; additive model: OR = 1.17, 95% CI = 1.08–1.28) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk remained for subgroups of bladder cancer and breast cancer, especially in Caucasians. In addition, significantly decreased lung cancer risk was also observed. In summary, this meta-analysis suggests the participation of XRCC3 T241M in the susceptibility for bladder cancer and breast cancer, especially in Caucasians, and XRCC3 T241M polymorphism is associated with decreased lung cancer risk. Moreover, our work also points out the importance of new studies for T241M association in some cancer types, such as gastric cancer, colorectal cancer, and melanoma skin cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the XRCC3 polymorphism in cancer development.