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Dendritic cell nuclear protein-1 (DCNP1) is a protein associated with major depression.In the brains of depression patients,DCNP1 is up-regulated.However,how DCNP1 participates in the pathogenesis of major depression remains unknown.In this study,we first transfected HEK293 cells with EGFP-DCNP1 and demonstrated that the full-length DCNP1 protein was localized in the nucleus,and RRK (the residues 117-119) composed its nuclear localization signal (NLS).An RRK-deletion form of DCNP1 (DCNP1△RRK) and truncated form (DCNP11-116),each lacking the RRK residues,did not show the specific nuclear localization like full-length DCNP1 in the cells.A rat glioma cell line C6 can synthesize melatonin,a hormone that plays important roles in both sleep and depression.We then revealed that transfection of C6 cells with full-length DCNP1 but not DCNP1△RRK or DCNP11-116 significantly decreased the levels of melatonin.Furthermore,overexpression of full-length DCNP1,but not DCNP1△RRK or DCNP11-116,in C6 cells significantly decreased both the mRNA and protein levels of N-acetyltransferase (NAT),a key enzyme in melatonin synthesis.Full-length DCNP1 but not DCNP1△RRK or DCNP11-116 was detected to interact with the Nat promoter and inhibited its activity through its E-box motif.Furthermore,full-length DCNP1 but not the mutants interacted with and repressed the transcriptional activity of BMAL1,a transcription factor that transactivates Nat through the E-box motif.In conclusion,we have shown that RRK (the residues 117-119) are the NLS responsible for DCNP1 nuclear localization.Nuclear DCNP1 represses NAT expression and melatonin biosynthesis by interacting with BMAL1 and repressing its transcriptional activity.Our study reveals a connection between the major depression candidate protein DCNP1,circadian system and melatonin biosynthesis,which may contribute to the pathogenesis of depression.