The Human Disease Ontology (DO) (www.disease-ontology.org) database, has significantly expanded the disease content and enhanced our userbase and website since the DO’s 2018 Nucleic Acids Research DATABASE issue paper. Conservatively, based on available resource statistics, terms from the DO have been annotated to over 1.5 million biomedical data elements and citations, a 10× increase in the past 5 years. The DO, funded as a NHGRI Genomic Resource, plays a key role in disease knowledge organization, representation, and standardization, serving as a reference framework for multiscale biomedical data integration and analysis across thousands of clinical, biomedical and computational research projects and genomic resources around the world. This update reports on the addition of 1,793 new disease terms, a 14% increase of textual definitions and the integration of 22 137 new SubClassOf axioms defining disease to disease connections representing the DO’s complex disease classification. The DO’s updated website provides multifaceted etiology searching, enhanced documentation and educational resources.

In eukaryotic organisms, the largely cytosolic copper and zinc containing superoxide dismutase enzyme (Cu/Zn SOD) represents a key defense against reactive oxygen toxicity. Although much is known about the biology of this enzyme under aerobic conditions, less is understood regarding the effects of low oxygen on Cu/Zn SOD from diverse organisms. We show here that like bakers’ yeast (Saccharomyces cerevisiae), adaptation of the multicellular Caenorhabditis elegans to growth in low oxygen involves strong down-regulation of its Cu/Zn SOD. Much of this regulation occurs at the post-translational level where CCS-independent activation of Cu/Zn SOD is inhibited. Hypoxia inactivates the endogenous Cu/Zn SOD of C. elegans Cu/Zn SOD as well as a P144 mutant of S. cerevisiae Cu/Zn SOD (herein denoted as Sod1p) that is independent of CCS. In our studies of S. cerevisiae Sod1p we noted a post-translational modification to the inactive enzyme during hypoxia. Analysis of this modification by mass spectrometry revealed phosphorylation on serine 38. Serine 38 represents a putative proline-directed kinase target site located on a solvent exposed loop that is positioned at one end of the Sod1p beta-barrel, a region immediately adjacent to residues previously shown to influence CCS-dependent activation. Although phosphorylation of serine 38 is minimal when the Sod1p is abundantly active (e.g., high oxygen), up to 50% of Sod1p can be phosphorylated when CCS-activation of the enzyme is blocked, e.g., by hypoxia or low copper conditions. Serine 38 phosphorylation can be a marker for inactive pools of Sod1p.

Background: During prolonged periods without glucose yeast cells acidify the extracellular environment. Results: This acid burst is derived from a mitochondrial aldehyde dehydrogenase and a cascade involving superoxide damage to the TCA cycle. Conclusion:The acid burst can condition the medium to improve cell growth. Significance: Damage from mitochondrial superoxide can be advantageous to cells during carbon starvation stress.

In eukaryotes, the Cu/Zn containing superoxide dismutase (SOD1) plays a critical role in oxidative stress protection as well as in signaling. We recently demonstrated a function for S. cerevisiae Sod1p in signaling through CK1γ casein kinases and identified the essential proton ATPase Pma1p as one likely target. The connection between Sod1p and Pma1p was explored further by testing the impact of sod1Δ mutations on cells expressing mutant alleles of Pma1p that alter activity and/or post-translational regulation of this ATPase. We report here that sod1Δ mutations are lethal when combined with the T912D allele of Pma1p in the C-terminal regulatory domain. This “synthetic lethality” was reversed by intragenic suppressor mutations in Pma1p, including an A906G substitution that lies within the C-terminal regulatory domain and hyper-activates Pma1p. Surprisingly the effect of sod1Δ mutations on Pma1-T912D is not mediated through the Sod1p signaling pathway involving the CK1γ casein kinases. Rather, Sod1p sustains life of cells expressing Pma1-T912D through oxidative stress protection. The synthetic lethality of sod1Δ Pma1-T912D cells is suppressed by growing cells under low oxygen conditions or by treatments with manganese-based antioxidants. We now propose a model in which Sod1p maximizes Pma1p activity in two ways: one involving signaling through CK1γ casein kinases and an independent role for Sod1p in oxidative stress protection.