[8][9][10] The Fbxl3 gene function was independently identified in 2007 by three groups, led by Michele Pagano, Joseph S. Takahashi, Dr. Patrick Nolan and Michael Hastings, respectively.

Takahashi used forward genetics N-ethyl-N-nitrosourea (ENU) mutagenesis to screen for mice with varied circadian activity which led to the discovery of the Overtime (Ovtm) mutant of the Fbxl3 gene.

[9] Nolan discovered the Fbxl3 mutation After hours (Afh) by a forward screen assessing wheel activity behavior of mutagenized mice.

Overtime is a loss of function mutation caused by a substitution of isoleucine to threonine in the region of FBXL3 that binds to CRY.

Predominantly localized to the cytosol, Fbxl21 has been proposed to antagonize the action of Fbxl3 through ubiquitination and stabilization of CRY proteins instead of leading it to degradation.

[14] The FBXL3 protein contains an F-box domain, characterized by a 40 amino acid motif that mediates protein-protein interactions, and several tandem leucine-rich repeats used for substrate recognition.

Bmal1 expression is regulated by the binding of REV-ERBα and RORα proteins to retinoic acid-related orphan receptor response elements (ROREs) in the Bmal1 promoter region.