Page 68 - F. Cell biology

[F. Cell biology-43]

Disrupted-in-schizophrenia 1 enhances the quality of

circadian rhythm by stabilizing BMAL1

Su Been Lee¹, Jihyun Park², Yongdo Kwak¹, Young-Un Park¹, Truong Thi My Nhung¹, Bo Kyoung Suh¹,
Youngsik Woo¹, Yeongjun Suh¹, Eunbyul Cho¹, Yubin Won¹, Tran Diem Nghi¹, Jinyeong Yoo¹, Hyeon ah Ji¹,

Sehyung Cho²˙*, Sang Ki Park¹˙*

¹Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea,
²Department of Physiology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea

Disrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that has been implicated in multiple mental disorders.
DISC1 is known to regulate neuronal proliferation, signaling, and intracellular calcium homeostasis, as well as
neurodevelopment. Although DISC1 was linked to sleep-associated behaviors, whether DISC1 functions in the

circadian rhythm has not been determined yet. In this work, we reveal that Disc1 expression exhibits daily oscillating
pattern and is regulated by binding of Circadian locomotor output cycles kaput (CLOCK) and Brain and muscle Arnt-

like protein-1 (BMAL1) heterodimer to E-box sequences in its promoter. Interestingly, Disc1 knockout increases the
ubiquitination of BMAL1 and de-stabilizes it, thereby reducing its protein levels. DISC1 inhibits the activity of GSK3β,

which promotes BMAL1 ubiquitination, suggesting that DISC1 regulates BMAL1 stability by inhibiting its
ubiquitination. Moreover, Disc1-deficient cells and mice show reduced expression of other circadian genes. Finally,

Disc1 knockout mice exhibit damped circadian physiology and behaviors. Collectively, these findings demonstrate
that the oscillation of DISC1 expression is under the control of CLOCK and BMAL1, and that DISC1 contributes to

the core circadian system by regulating BMAL1 stability.