Identification and functional implication of nuclear localization signals in the N-terminal domain of JMJD5.

JMJD5 has recently been reported to participate in circadian rhythm regulation, embryological development, osteoclastogenesis and tumorigenesis. Although JMJD5 has been found mainly localized in the nucleus of cells, how it enters the nucleus remains unclear. Here we report that JMJD5 contains a functional bipartite nuclear localization signal (NLS) and a chromosome region maintenance 1 (CRM1)-dependent nuclear export signal (NES). Importin α/β and transportin-1 were further identified as JMJD5-associated transport proteins, and different binding regions were determined for the two nuclear import receptors. Additionally, we demonstrate that both the active NLS and the JmjC domain of JMJD5 are necessary for cyclin A1 transcription. Chromatin immunoprecipitation (ChIP) analysis confirmed the alterations of di-methylated lysine 36 of histone H3 (H3K36me2) in the coding region of cyclin A1. These results reveal that the N-terminal domain is essential for the nuclear localization of JMJD5 and its normal enzymatic function towards substrates in the nucleus.