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Ubiquitin-mediated processes orchestrate critical DNA-damage signaling and repair pathways. We identify human DVC1 (C1orf124; Spartan) as a cell cycle-regulated anaphase-promoting complex (APC) substrate that accumulates at stalled replication forks. DVC1 recruitment to sites of replication stress requires its ubiquitin-binding UBZ domain and PCNA-binding PIP box motif but is independent of RAD18-mediated PCNA monoubiquitylation. Via a conserved SHP box, DVC1 recruits the ubiquitin-selective chaperone p97 to blocked replication forks, which may facilitate p97-dependent removal of translesion synthesis (TLS) DNA polymerase η (Pol η) from monoubiquitylated PCNA. DVC1 knockdown enhances UV light-induced mutagenesis, and depletion of human DVC1 or the Caenorhabditis elegans ortholog DVC-1 causes hypersensitivity to replication stress-inducing agents. Our findings establish DVC1 as a DNA damage-targeting p97 adaptor that protects cells from deleterious consequences of replication blocks and suggest an important role of p97 in ubiquitin-dependent regulation of TLS.

Dynamic metabolic changes occurring in neurons are critically important in directing brain plasticity and cognitive function. In other tissue types, disruptions to metabolism and the resultant changes in cellular oxidative state, such as increased reactive oxygen species (ROS) or induction of hypoxia, are associated with cellular stress. In the brain however, where drastic metabolic shifts occur to support physiological processes, subsequent changes to cellular oxidative state and induction of transcriptional sensors of oxidative stress likely play a significant role in regulating physiological neuronal function. Understanding the role of metabolism and metabolically-regulated genes in neuronal function will be critical in elucidating how cognitive functions are disrupted in pathological conditions where neuronal metabolism is affected. Here, we discuss known mechanisms regulating neuronal metabolism as well as the role of hypoxia and oxidative stress during normal and disrupted neuronal function. We also summarize recent studies implicating a role for metabolism in regulating neuronal plasticity as an emerging neuroscience paradigm.

SUMMARY Background Even though functional lateralization is a predominant feature of many nervous systems, it is poorly understood how lateralized neural function is linked to lateralized gene activity. A bilaterally symmetric pair of gustatory neurons in the nematode C. elegans, ASEL and ASER, serves as a model to study the genetic basis of functional lateralization as this pair senses a number of chemicals in a left/right asymmetric manner. The extent of functional lateralization of the ASE neurons and genes responsible for the left/right asymmetric activity of ASEL/R are unknown. Results We show here that a large panel of salt ions is sensed in a left/right asymmetric manner, as demonstrated by behavioral assays, imaging of neural activity with a genetically encoded calcium sensor and by genetic manipulations that alter the fate of either ASEL or ASER. We show that lateralized salt responses allow the worm to discriminate between distinct salt cues. To identify molecules that may be involved in sensing salt ions and/or transmitting such sensory information, we examined the chemotaxis behavior of animals harboring mutations in eight different receptor-type, transmembrane guanylyl cyclases (encoded by gcy genes), which are expressed in either ASEL (gcy-6, gcy-7, gcy-14), ASER (gcy-1, gcy-4, gcy-5, gcy-22) or ASEL and ASER (gcy-19). Disruption of a ASER-expressed gcy gene, gcy-22, resulted in a broad chemotaxis defect to nearly all salts sensed by ASER, as well as to a left/right-asymmetrically sensed amino acid. In contrast, disruption of other gcy genes resulted in highly salt ion-specific chemosensory defects. Furthermore, we show that not only the cyclase domain, but also the extracellular domain of GCY proteins is important for their activity in salt sensation. Conclusions Our findings broaden our understanding of lateralities in neural function, provide insights into how this laterality is molecularly encoded and reveal an unusually diverse spectrum of signaling molecules involved in gustatory signal transduction.