During stress, a protective cellular network known as the heat shock response (HSR) is induced to maintain protein-folding homeostasis, or proteostasis. While the HSR is essential for stress resistance, its misregulation is associated with cancer. Using a genome-wide RNAi screen, we identified
dcp-66, a subunit of the nucleosome remodeling and deacetylase (NuRD) complex, as a new positive regulator of the HSR. We found that RNAi knockdown of
dcp-66 leads to repression of the HSR exclusively during young adulthood, before the HSR collapses with the onset of reproductive maturity. Furthermore,
dcp-66 inhibition prevents the collapse of the HSR with the transition to gravid adulthood. To test if these effects are mediated by other subunits of NuRD, we measured induction of the HSR in worms containing mutations in either
chd-3 or
let-418, as these are the unique catalytic cores that define the two NuRD complexes in C. elegans. We found that mutations in
let-418 but not
chd-3 affected the HSR. However, in contrast to the positive regulation of the HSR by
dcp-66, our data indicate that
let-418 is a negative HSR regulator. These results suggest an unexpected regulatory role for
dcp-66 within the
let-418 NuRD complex. To investigate this dichotomy further, we examined the role of
dcp-66 and
let-418 in other stress responses and found similar, antagonistic effects between the two subunits in the oxidative stress response (
gst-4), insulin-like signaling (
sod-3), and the DNA damage response (
egl-1). Together, our work indicates that negative regulation of stress response pathways by the
let-418 NuRD complex is a general phenomenon, and that the
dcp-66 subunit of NuRD has a positive, regulatory role when these pathways are induced. Intriguingly, several NuRD subunits are misregulated and/or mutated during cancer; therefore, elucidating this pathway could help explain how the HSR becomes misregulated during cancer.