In a twist to an established story, the termination of noncoding RNAs by the NNS complex (NRD1 snoRNA termination complex) appears to be dependent on the phosphorylation of a regulatory component. In a 2022 issue of Nucleic Acids Research, Haidara et al. show how the NNS-complex component Sen1p acts to repress transcription of the zinc master regulator ZAP1 when Sen1p is phosphorylated, which appears to happen in response to excess zinc.
The NNS complex had previously been shown to terminate transcription of PHO84 via antisense RNA. In Haidara et al., the authors identify the previously unannotated noncoding RNA ZRN1 as lying directly upstream of ZAP1 and, when transcribed without termination, repressing the downstream gene. Termination of ZRN1 transcription by dephosphophorylated Sen1p derepresses ZAP1 mRNA levels via removal of the interfering RNA. As evidence of this relationship, a Sen1p phospho-mimetic mutation (T1623E) results in stable repression of ZAP1 transcription.
Working model for Sen1p regulation of gene expression, from Haidara et al.
The model proposed is that zinc excess leads to phosphorylation of Sen1p by an unidentified kinase, which then causes the level of ZRN1 transcript to increase because termination is impaired. This in turn represses ZAP1 mRNA levels by interference, thereby repressing genes responsible for increased zinc uptake and storage.
Interestingly, the same system (i.e. Sen1p as a component of the NNS complex) represses PHO84 expression via interference, and PHO84 encodes a low-affinity Zn transporter that also contributes to zinc homeostasis. Might RNA interference play an expanded regulatory role over what is currently known?