KDM8

Description

The KDM8 (lysine demethylase 8) is a protein-coding gene located on chromosome 16.

The KDM8 gene in humans encodes a protein called lysine demethylase 8. It is believed to function as a histone lysine demethylase. Studies on a similar protein in mice suggest that KDM8 could act as a tumor suppressor. Multiple transcript variants have been identified for this gene.

KDM8 is a bifunctional enzyme that acts as both an endopeptidase and a 2-oxoglutarate-dependent monooxygenase. As an endopeptidase, it cleaves histone N-terminal tails at the carboxyl side of methylated arginine or lysine residues, generating 'tailless nucleosomes' which may trigger transcription elongation. It preferentially recognizes and cleaves monomethylated and dimethylated arginine residues of histones H2, H3 and H4. After initial cleavage, it continues to digest histone tails via its aminopeptidase activity. Upon DNA damage, it cleaves the N-terminal tail of histone H3 at monomethylated lysine residues, preferably at monomethylated 'Lys-9' (H3K9me1). The histone variant H3F3A is the major target for cleavage. Additionally, KDM8 acts as a Fe(2+) and 2-oxoglutarate-dependent monooxygenase, catalyzing (R)-stereospecific hydroxylation at C-3 of 'Arg-137' of RPS6 and 'Arg-141' of RCCD1, although the biological significance of this activity remains to be established. KDM8 regulates mitosis through various mechanisms: it plays a role in transcriptional repression of satellite repeats, possibly by regulating H3K36 methylation levels in centromeric regions together with RCCD1. Possibly together with RCCD1, it is involved in proper mitotic spindle organization and chromosome segregation. KDM8 negatively regulates the cell cycle repressor CDKN1A/p21, which controls G1/S phase transition. It is required for G2/M phase cell cycle progression. It regulates the expression of CCNA1/cyclin-A1, leading to cancer cell proliferation. KDM8 also plays a role in regulating alpha-tubulin acetylation and cytoskeletal microtubule stability involved in epithelial to mesenchymal transition. It regulates circadian gene expression in the liver. It represses the transcriptional activator activity of the CLOCK-BMAL1 heterodimer in a catalytically-independent manner. KDM8 negatively regulates the protein stability and function of CRY1; it is required for AMPK-FBXL3-induced CRY1 degradation.

KDM8 is also known as JMJD5.

Associated Diseases

WES Whole Exome Sequencing