DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα

The nuclear receptor Rev-erb alpha has been implicated as a major regulator of the circadian clock and integrates circadian rhythm and metabolism. Rev-erb alpha controls circadian oscillations of several clock genes and Rev-erb alpha protein degradation is important for maintenance of the circadian oscillations and also for adipocyte differentiation. Elucidating the mechanisms that regulate Rev-erb alpha stability is essential for our understanding of these processes. In the present paper, we report that the protein DBC1 (Deleted in Breast Cancer 1) is a novel regulator of Rev-erb alpha Rev-erb alpha and DBC1 interact in cells and in vivo, and DBC1 modulates the Rev-erba repressor function. Depletion of DBC1 by siRNA (small interfering RNA) in cells or in DBC1-KO (knockout) mice produced a marked decrease in Rev-erb alpha protein levels, but not in mRNA levels. In contrast, DBC1 overexpression significantly enhanced Rev-erb alpha protein stability by preventing its ubiquitination and degradation. The regulation of Rev-erb alpha protein levels and function by DBC1 depends on both the N-terminal and C-terminal domains of DBC1. More importantly, in cells depleted of DBC1, there was a dramatic decrease in circadian oscillations of both Rev-erb alpha and BMAL1. In summary, our data identify DBC1 as an important regulator of the circadian receptor Rev-erb alpha and proposes that Rev-erb alpha could be involved in mediating some of the physiological effects of DBC1.