Living with p53, dying of p53

The p53 tumor suppressor protein acts as a major defense against cancer. Among its most distinctive features is the ability to elicit both apoptotic death and cell cycle arrest. In this issue of Cell, Das et al. (2007) and Tanaka et al. (2007) provide new insights into the mechanisms that dictate the life and death decisions of p53.     

Scavenger receptor C-type lectin binds to the leukocyte cell surface glycan Lewis(x) by a novel mechanism

The scavenger receptor C-type lectin (SRCL) is unique in the family of class A scavenger receptors, because in addition to binding sites for oxidized lipoproteins it also contains a C-type carbohydrate-recognition domain (CRD) that interacts with specific glycans. Both human and mouse SRCL are highly specific for the Lewis(x) trisaccharide, which is commonly found on the surfaces of leukocytes and some tumor cells. Structural analysis of the CRD of mouse SRCL in complex with Lewis(x) and mutagenesis show the basis for this specificity. The interaction between mouse SRCL and Lewis(x) is analogous to the way that selectins and DC-SIGN bind to related fucosylated glycans, but the mechanism of the interaction is novel, because it is based on a primary galactose-binding site similar to the binding site in the asialoglycoprotein receptor. Crystals of the human receptor lacking bound calcium ions reveal an alternative conformation in which a glycan ligand would be released during receptor-mediated endocytosis.     

Does distance matter? Variations in alternative 3′ splicing regulation

Alternative splicing constitutes a major mechanism creating protein diversity in humans. This diversity can result from the alternative skipping of entire exons or by alternative selection of the 5′ or 3′ splice sites that define the exon boundaries. In this study, we analyze the sequence and evolutionary characteristics of alternative 3′ splice sites conserved between human and mouse genomes for distances ranging from 3 to 100 nucleotides. We show that alternative splicing events can be distinguished from constitutive splicing by a combination of properties which vary depending on the distance between the splice sites. Among the unique features of alternative 3′ splice sites, we observed an unexpectedly high occurrence of events in which a polypyrimidine tract was found to overlap the upstream splice site. By applying a machine-learning approach, we show that we can successfully discriminate true alternative 3′ splice sites from constitutive 3′ splice sites. Finally, we propose that the unique features of the intron flanking alternative splice sites are indicative of a regulatory mechanism that is involved in splice site selection. We postulate that the process of splice site selection is influenced by the distance between the competitive splice sites.     

Raised salivary testosterone in women is associated with increased attraction to masculine faces

Women's preferences for masculinity in men's faces, voices and behavioral displays change during the menstrual cycle and are strongest around ovulation. While previous findings suggest that change in progesterone level is an important hormonal mechanism for such variation, it is likely that changes in the levels of other hormones will also contribute to cyclic variation in masculinity preferences. Here we compared women's preferences for masculine faces at two points in the menstrual cycle where women differed in salivary testosterone, but not in salivary progesterone or estrogen. Preferences for masculinity were strongest when women's testosterone levels were relatively high. Our findings complement those from previous studies that show systematic variation in masculinity preferences during the menstrual cycle and suggest that change in testosterone level may play an important role in cyclic shifts in women's preferences for masculine traits.     

Aeromonas salmonicida toxin AexT has a Rho family GTPase-activating protein domain

The N terminus of the Aeromonas salmonicida ADP-ribosylating toxin AexT displays in vitro GTPase-activating protein (GAP) activity for Rac1, CDC42, and RhoA. HeLa cells transfected with the AexT N terminus exhibit rounding and actin disordering. We propose that the Aeromonas salmonicida AexT toxin is a novel member of the growing family of bacterial RhoGAPs.     

Engineered antifouling microtopographies - effect of feature size, geometry, and roughness on settlement of zoospores of the green alga Ulva

The effect of feature size, geometry, and roughness on the settlement of zoospores of the ship fouling alga Ulva was evaluated using engineered microtopographies in polydimethylsiloxane elastomer. The topographies studied were designed at a feature spacing of 2 microm and all significantly reduced spore settlement compared to a smooth surface. An indirect correlation between spore settlement and a newly described engineered roughness index (ERI) was identified. ERI is a dimensionless ratio based on Wenzel's roughness factor, depressed surface fraction, and the degree of freedom of spore movement. Uniform surfaces of either 2 mum diameter circular pillars (ERI=5.0) or 2 microm wide ridges (ERI=6.1) reduced settlement by 36% and 31%, respectively. A novel multi-feature topography consisting of 2 mum diameter circular pillars and 10 microm equilateral triangles (ERI=8.7) reduced spore settlement by 58%. The largest reduction in spore settlement, 77%, was obtained with the Sharklet AF topography (ERI=9.5).     

Where do these bugs come from? Phenotypic structure of Triatoma infestans populations after control interventions in the Argentine Chaco

House re-invasion by native triatomines after insecticide-based control campaigns represents a major threat for Chagas disease vector control. We conducted a longitudinal intervention study in a rural section (Area III, 407 houses) of Pampa del Indio, northeastern Argentina, and used wing geometric morphometry to compare pre-spray and post-spray (re-infestant bugs) Triatoma infestans populations. The community-wide spraying with pyrethroids reduced the prevalence of house infestation by T. infestans from 31.9% to < 1% during a four-year follow-up, unlike our previous studies in the neighbouring Area I. Two groups of bug collection sites differing in wing shape variables before interventions (including 221 adults from 11 domiciles) were used as a reference for assigning 44 post-spray adults. Wing shape variables from post-spray, high-density bug colonies and pre-spray groups were significantly different, suggesting that re-infestant insects had an external origin. Insects from one house differed strongly in wing shape variables from all other specimens. A further comparison between insects from both areas supported the existence of independent re-infestation processes within the same district. These results point to local heterogeneities in house re-infestation dynamics and emphasise the need to expand the geographic coverage of vector surveillance and control operations to the affected region.     

The COP9 signalosome is vital for timely repair of DNA double-strand breaks

The DNA damage response is vigorously activated by DNA double-strand breaks (DSBs). The chief mobilizer of the DSB response is the ATM protein kinase. We discovered that the COP9 signalosome (CSN) is a crucial player in the DSB response and an ATM target. CSN is a protein complex that regulates the activity of cullin ring ubiquitin ligase (CRL) complexes by removing the ubiquitin-like protein, NEDD8, from their cullin scaffold. We find that the CSN is physically recruited to DSB sites in a neddylation-dependent manner, and is required for timely repair of DSBs, affecting the balance between the two major DSB repair pathways—nonhomologous end-joining and homologous recombination repair (HRR). The CSN is essential for the processivity of deep end-resection—the initial step in HRR. Cullin 4a (CUL4A) is recruited to DSB sites in a CSN- and neddylation-dependent manner, suggesting that CSN partners with CRL4 in this pathway. Furthermore, we found that ATM-mediated phosphorylation of CSN subunit 3 on S410 is critical for proper DSB repair, and that loss of this phosphorylation site alone is sufficient to cause a DDR deficiency phenotype in the mouse. This novel branch of the DSB response thus significantly affects genome stability.     

Silencing the mob: disrupting quorum sensing as a means to fight plant disease

Bacteria are able to sense their population's density through a cell–cell communication system, termed ‘quorum sensing’ (QS). This system regulates gene expression in response to cell density through the constant production and detection of signalling molecules. These molecules commonly act as auto‐inducers through the up‐regulation of their own synthesis. Many pathogenic bacteria, including those of plants, rely on this communication system for infection of their hosts. The finding that the countering of QS‐disrupting mechanisms exists in many prokaryotic and eukaryotic organisms offers a promising novel method to fight disease. During the last decade, several approaches have been proposed to disrupt QS pathways of phytopathogens, and hence to reduce their virulence. Such studies have had varied success in vivo, but most lend promising support to the idea that QS manipulation could be a potentially effective method to reduce bacterial‐mediated plant disease. This review discusses the various QS‐disrupting mechanisms found in both bacteria and plants, as well as the different approaches applied artificially to interfere with QS pathways and thus protect plant health.