KDM5A
Description
The KDM5A (lysine demethylase 5A) is a protein-coding gene located on chromosome 12.
Lysine-specific demethylase 5A is an enzyme that in humans is encoded by the KDM5A gene. The protein encoded by this gene is a ubiquitously expressed nuclear protein. It binds directly, with several other proteins, to retinoblastoma protein which regulates cell proliferation. It was formerly known as Retinoblastoma Binding Protein 2 (RBP2). This protein also interacts with rhombotin-2 which functions distinctly in erythropoiesis and in T-cell leukemogenesis. Rhombotin-2 is thought to either directly affect the activity of the encoded protein or may indirectly modulate the functions of the retinoblastoma protein by binding to this protein. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. The Drosophila homolog, LID, was found to be an H3K4 histone demethylase that binds to c-Myc. It was recently renamed to Lysine Demethylase 5 (KDM5). Enzymatically can be designated as a trimethyllysine dioxygenase, which is a member of the alpha-ketoglutarate-dependent hydroxylase superfamily (EC 1.14.11.8).
KDM5A is a histone demethylase that specifically removes methyl groups from the fourth lysine residue (Lys-4) of histone H3. This plays a crucial role in the histone code, a system of modifications that regulate gene expression. KDM5A doesn't demethylate other lysine residues on histone H3 (Lys-9, Lys-27, Lys-36, Lys-79) or Lys-20 on histone H4. It can remove both dimethyl and trimethyl groups from H3 Lys-4, but not monomethyl groups. KDM5A regulates gene transcription by directly binding to a specific DNA sequence, 5'-CCGCCC-3', and may also enhance transcription mediated by nuclear receptors. It is involved in regulating the expression of Hox genes during cell differentiation. KDM5A might repress the transcription of certain cytokines, such as CXCL12. Additionally, it plays a role in regulating circadian rhythms and maintaining the normal periodicity of the circadian clock. Independent of its demethylase activity, KDM5A acts as a coactivator for the CLOCK-BMAL1 complex, which activates the transcription of genes like PER1/2 and other clock-controlled genes. By inhibiting HDAC1 activity, KDM5A increases histone acetylation at the PER1/2 promoters. KDM5A can also act as a transcriptional corepressor for some genes, like MT1F, and might promote cancer cell proliferation. KDM5A interacts directly with SUZ12 and the viral protein-binding domain of RB1. It interacts with ESR1, MYC, MYCN, LMO2, and HDAC1, impairing HDAC1's deacetylation activity. It also interacts with BMAL1 and CLOCK. Finally, KDM5A interacts with unmodified H3 Lys-4 through its PHD-type 1 zinc finger and with di- and trimethylated H3 Lys-4 through its PHD-type 3 zinc finger.
KDM5A is also known as NEDEHC, RBBP-2, RBBP2, RBP2.
