A gene pair termed
numr-1/2 (nuclear-localized metal-responsive) was previously shown to encode an SR-like protein with an RNA-recognition motif that promotes longevity and growth in cadmium. We recently used a genome-wide screen to demonstrate that
numr-1/2 is activated by disruption of RNA metabolism. To investigate
numr-1/2 regulation and identify modulators of nucleic acid metabolism, we screened over 40,000 compounds and extracts from commercial and natural product libraries for
numr-1/2p::GFP activation. We identified six
numr-1/2 inducers; three (floxuridine, 5-fluouracil, and actinomycin D) have well-characterized effects on DNA and RNA confirming that
numr-1/2 is regulated by changes in nucleic acid metabolism. Fungal toxin chaetocin was the most potent and least toxic
numr-1/2 inducer. RT-qPCR demonstrates that chaetocin induces
numr-1/2 and another stress-responsive SR-like protein gene (W03G1.5) over 50-fold within 45 minutes without affecting expression of canonical heat shock, osmotic stress, endoplasmic reticulum stress, mitochondrial stress, or detoxification response genes. Chaetocin does not activate other metal-responsive genes and actually reduces expression of metallothionein gene
mtl-2 and fluorescence of
mtl-2p::GFP consistent with repression of
mtl-2 transcription. A time-course experiment demonstrated that induction of
numr-1/2 precedes decreases in
mtl-2 by 1-2 hours. We find that
numr-1/2 is required for chaetocin to repress
mtl-2 fully, consistent with NUMR-1/2 negatively regulating
mtl-2 transcription. Chaetocin is a promising anticancer candidate in cell culture and in vivo models; it was first shown to inhibit histone lysine methyltransferase (HMT) SU(VAR)3-9 and later shown to affect thioredoxin reductase. Robust activation of
numr-1/2 in C. elegans provides an opportunity to harness genetic tractability to gain new insights into chaetocin bioactivity. Using a
trxr-1/2 double mutant, we find that chaetocin induces
numr-1/2 independently of thioredoxin reductase. C. elegans has over 35 predicted HMTs; we are now testing HMT mutants for induction of
numr-1/2. Our results raise the possibility that histone methylation dynamically regulates stress-responsive genes in terminally differentiated somatic cells. This work was supported by NSF grant IOS-1452948 and a UF Research Opportunity Seed Fund Grant to KPC, CWW, and HL.