Proteins of the Homeodomain-Interacting Protein Kinase (HIPK) family regulate an array of processes in mammalian systems, such as the DNA damage response, cellular proliferation and apoptosis. The nematode Caenorhabditis elegans has a single HIPK homologue called HPK-1. Previous studies have implicated HPK-1 in longevity control and suggested that this protein may be regulated in a stress-dependent manner. Here we set out to expand these observations by investigating the role of HPK-1 in longevity and in the response to heat and oxidative stress. We find that levels of HPK-1 are regulated by heat stress, and that HPK-1 contributes to survival following heat or oxidative stress. Additionally, we show that HPK-1 is required for normal longevity, with loss of HPK-1 function leading to a faster decline of physiological processes that reflect premature ageing. Through microarray analysis, we have found that HPK-1-regulated genes include those encoding proteins that serve important functions in stress responses such as Phase I and Phase II detoxification enzymes. Consistent with a role in longevity assurance, HPK-1 also regulates the expression of age-regulated genes. Lastly, we show that HPK-1 functions in the same pathway as DAF-16 to regulate longevity and reveal a new role for HPK-1 in development.

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Chromatin regulators contribute to the developmental control of gene expression. In the nematode Caenorhabditis elegans, the roles of chromatin regulation in development have been explored in several contexts, including vulval differentiation. The synthetic multivulva (synMuv) genes are regulators of vulval development in C. elegans and the proteins encoded by these genes include components of several histone modification and chromatin remodelling complexes. By inhibiting ectopic expression of the epidermal growth factor (LIN-3) in the nematode hypodermis, the synMuv genes prevent inappropriate vulval induction. In a forward genetic screen for modifiers of the expression of a hypodermal reporter gene, we identified a mutation that results in increased expression of the reporter. This mutation also suppresses ectopic vulval induction in synMuv mutants and we have consequently named the affected gene suppressor of synthetic multivulva-1 (sumv-1). We show that SUMV-1 is required in the hypodermis for the synMuv phenotype and that loss of sumv-1 function suppresses ectopic expression of lin-3 in synMuv mutant animals. In yeast two-hybrid assays SUMV-1 physically interacts with SUMV-2, and reduction of sumv-2 function also suppresses the synMuv phenotype. We identified similarities between SUMV-1 and SUMV-2 and mammalian proteins KAT8 NSL2 and KAT8 NSL3, respectively, which are components of the KAT8/MOF histone acetyltransferase complex. Reduction of function of mys-2, which encodes the enzymatic component of the KAT8/MOF complex, also suppresses the synMuv phenotype, and MYS-2 physically interacts with SUMV-2 in yeast two-hybrid assays. Together these observations suggest that SUMV-1 and SUMV-2 may function together with MYS-2 in a nematode KAT8/MOF-like complex to antagonise the activity of the synMuv genes.