Suppression of cytokine signaling: The SOCS perspective

The discovery of the Suppressor of Cytokine Signaling (SOCS) family of proteins has resulted in a significant body of research dedicated to dissecting their biological functions and the molecular mechanisms by which they achieve potent and specific inhibition of cytokine and growth factor signaling. The Australian contribution to this field has been substantial, with the initial discovery of SOCS1 by Hilton, Starr and colleagues (discovered concurrently by two other groups) and the following work, providing a new perspective on the regulation of JAK/STAT signaling. In this review, we reflect on the critical discoveries that have lead to our current understanding of how SOCS proteins function and discuss what we see as important questions for future research.     

Separation of intra-S checkpoint protein contributions to DNA replication fork protection and genomic stability in normal human fibroblasts

The ATR-dependent intra-S checkpoint protects DNA replication forks undergoing replication stress. The checkpoint is enforced by ATR-dependent phosphorylation of CHK1, which is mediated by the TIMELESS-TIPIN complex and CLASPIN. Although loss of checkpoint proteins is associated with spontaneous chromosomal instability, few studies have examined the contribution of these proteins to unchallenged DNA metabolism in human cells that have not undergone carcinogenesis or crisis. Furthermore, the TIMELESS-TIPIN complex and CLASPIN may promote replication fork protection independently of CHK1 activation. Normal human fibroblasts (NHF) were depleted of ATR, CHK1, TIMELESS, TIPIN or CLASPIN and chromosomal aberrations, DNA synthesis, activation of the DNA damage response (DDR) and clonogenic survival were evaluated. This work demonstrates in NHF lines from two individuals that ATR and CHK1 promote chromosomal stability by different mechanisms that depletion of CHK1 produces phenotypes that resemble more closely the depletion of TIPIN or CLASPIN than the depletion of ATR, and that TIMELESS has a distinct contribution to suppression of chromosomal instability that is independent of its heterodimeric partner, TIPIN. Therefore, ATR, CHK1, TIMELESS-TIPIN and CLASPIN have functions for preservation of intrinsic chromosomal stability that are separate from their cooperation for activation of the intra-S checkpoint response to experimentally induced replication stress. These data reveal a complex and coordinated program of genome maintenance enforced by proteins known for their intra-S checkpoint function.     

FBXL2 is a ubiquitin E3 ligase subunit that triggers mitotic arrest

Mitotic progression is regulated by ubiquitin E3 ligase complexes to carefully orchestrate eukaryotic cell division. Here, we show that a relatively new E3 ligase component belonging to the SCF (Skip-Cullin1-F-box protein) E3 ligase family, SCF^FBXL2, impairs cell proliferation by mediating cyclin D3 polyubiquitination and degradation. Both cyclin D3 and FBXL2 colocalize within the centrosome. FBXL2 overexpression led to G₂/M-phase arrest in transformed epithelia, resulting in the appearance of supernumerary centrosomes, tetraploidy and nuclei where condensed chromosomes are arranged on circular monopolar spindles typical of mitotic arrest. RNAi-mediated knockdown of cyclin D3 recapitulated effects of SCF^FBXL2 expression. SCF^FBXL2 impaired the ability of cyclin D3 to associate with centrosomal assembly proteins [Aurora A, polo-like kinase 4 (Plk4), CDK11]. Thus, these results suggest a role for SCF^FBXL2 in regulating the fidelity of cellular division.     

The N-end rule proteolytic system in autophagy

The N-end rule pathway is a cellular proteolytic system that utilizes specific N-terminal residues as degradation determinants, called N-degrons. N-degrons are recognized and bound by specific recognition components (N-recognins) that mediate polyubiquitination of low-abundance regulators and selective proteolysis through the proteasome. Our earlier work identified UBR4/p600 as one of the N-recognins that promotes N-degron-dependent proteasomal degradation. In this study, we show that UBR4 is associated with cellular cargoes destined to autophagic vacuoles and is degraded by the lysosome. UBR4 loss causes multiple misregulations in autophagic pathways, including an increased formation of LC3 puncta. UBR4-deficient mice die during embryogenesis primarily due to defective vascular development in the yolk sac (YS), wherein UBR4 is associated with a bulk lysosomal degradation system that absorbs maternal proteins from the YS cavity and digests them into amino acids. Our results suggest that UBR4 plays a role not only in selective proteolysis of short-lived regulators through the proteasome, but also bulk degradation through the lysosome. Here, we discuss a possible mechanism of UBR4 as a regulatory component in the delivery of cargoes destined to interact with the autophagic core machinery.     

Are Sage-Grouse Fine-Scale Specialists or Shrub-Steppe Generalists?

Sage-grouse (Centrocercus spp.) are influencing rapidly evolving land management policy in the western United States. Management objectives for fine-scale vegetation characteristics (e.g., grass height >18 cm) have been adopted by land management agencies based on resource selection or relationships with fitness proxies reported among numerous habitat studies. Some managers, however, have questioned the appropriateness of these objectives. Moreover, it remains untested whether habitat–fitness relationships documented at fine scales (i.e., among individual nests within a study area) also apply at scales of management units (e.g., pastures or grazing allotments), which are many orders of magnitude larger. We employed meta-analyses of studies published from 1991 to 2019 to help resolve the role of fine-scale vegetation structure in nest site selection and nest success across the geographic range of greater sage-grouse (C. urophasianus) and evaluate the validity of established habitat management objectives. Specifically, we incorporated effects of study design and functional responses to resource availability in meta-regression models linking vegetation structure to nest site selection, and used a novel meta-analytic approach to simultaneously model vegetation structure and its relationship to nest success. Our approach tested habitat relationships at a range-wide extent and a grain size closely matching scales at which agencies make management decisions. We found moderate, but context-dependent, effects of shrub characteristics and weak effects of herbaceous vegetation on nest site selection. None of the tested vegetation characteristics were related to variation in nest success, suggesting nesting habitat–fitness relationships have been inappropriately extrapolated in developing range-wide habitat management objectives. Our findings reveal surprising flexibility in habitat use for a species often depicted as having very particular fine-scale habitat requirements, and cast doubt on the practice of adopting precise management objectives for vegetation structure based on findings of individual small-scale field studies. © 2020 The Authors. The Journal of Wildlife Management published by Wiley Periodicals, Inc. on behalf of The Wildlife Society.     

Opportunistic Predation of Wild Turkey Nests by Wild Pigs

Wild pigs (Sus scrofa; i.e., feral hogs, feral swine) are considered an invasive species in the United States. Where they occur, they damage agricultural crops and wildlife habitat. Wild pigs also depredate native wildlife, particularly ground-nesting bird species during nesting season. In areas inhabited by wild turkeys (Meleagris gallopavo), nest destruction caused by wild pigs may affect recruitment. There is debate whether wild pigs actively seek ground-nesting bird nests or depredate them opportunistically. To address this debate, in 2016 we examined the movements of wild pigs relative to artificial wild turkey nests (i.e., control [no artificial nests], moderate density [12.5–25 nests/km²], and high density [25–50 nests/km²]) throughout the nesting season (i.e., early, peak, and late) in south-central Texas, USA. We found no evidence that wild pigs learned to seek and depredate wild turkey nests relative to nest density or nesting periods. Despite wild pigs being important nest predators, depredation was not a functional response to a pulsed food resource and can only be associated with overlapping densities of wild pigs and nests. Protecting reproductive success of wild turkeys will require reducing wild pig densities in nesting habitat prior to nesting season. © 2019 The Wildlife Society.     

Spatial Ecology and Resource Selection of Eastern Box Turtles

Eastern box turtles (Terrapene carolina carolina) are widely distributed throughout the eastern United States. Although once common throughout much of its distribution, the species has experienced declines in local populations. Understanding resource selection is important for the conservation of this species; however, few data exist on resource selection for eastern box turtles in the southeastern United States. We estimated home range and resource selection for 100 individual turtles in the Blue Ridge, Ridge and Valley, and Cumberland Plateau and Mountains physiographic regions in Tennessee, USA, from 2016 to 2018. We used step-selection functions to investigate eastern box turtle resource selection during May–August 2017 and May–August 2018 at 2 spatial scales. We classified vegetation type, measured vegetation composition and structure, recorded time since fire, and measured coarse woody debris abundance at 1,225 used telemetry locations and 1,225 associated available points. Home range sizes averaged 9.3 ha ± 3.0 (SE) using minimum convex polygon analysis, 8.25 ha ± 2.88 using 95% kernel density analysis, and 1.50 ha ± 0.56 using 50% kernel density analysis. Box turtles selected areas with greater visual obstruction at the 0–0.25-m level, greater amounts of 10-hour and 100-hour fuels (timelag categories used in fire-danger ratings), and greater litter depths compared to available locations. Box turtles were more likely to select areas with greater cover of brambles and coarser woody debris and were less likely to select areas with less vegetation cover. Vegetation type and time since last fire did not affect selection. Our data suggest that management activities that encourage greater understory vegetation cover, greater visual obstruction at the 0–0.25-m level, and greater bramble cover will enhance habitat quality for eastern box turtles. © 2020 The Wildlife Society.     

Factors,mechanisms and implications of chromatin condensation and chromosomal structural maintenance through the cell cycle

A series of well-orchestrated events help in the chromatin condensation and the formation of chromosomes. Apart from the formation of chromosomes, maintenance of their structure is important, especially for the cell division. The structural maintenance of chromosome (SMC) proteins, the non-SMC proteins and the SMC complexes are critical for the maintenance of chromosome structure. While condensins have roles for the DNA compaction, organization, and segregation, the cohesin functions in a cyclic manner through the cell cycle, as a “cohesin cycle.” Specific mechanisms maintain the architecture of the centromere, the kinetochore and the telomeres which are in tandem with the cell cycle checkpoints. The presence of chromosomal territories and compactness differences through the length of the chromosomes might have implications on selective susceptibility of specific chromosomes for induced genotoxicity.