KDM5A

Official Full Name

lysine demethylase 5A

Organism

Homo sapiens

GeneID

5927

Background

This gene encodes a member of the Jumonji, AT-rich interactive domain 1 (JARID1) histone demethylase protein family. The encoded protein plays a role in gene regulation through the histone code by specifically demethylating lysine 4 of histone H3. The encoded protein interacts with many other proteins, including retinoblastoma protein, and is implicated in the transcriptional regulation of Hox genes and cytokines. This gene may play a role in tumor progression. [provided by RefSeq, Aug 2013]

Synonyms

RBP2; RBBP2; NEDEHC; RBBP-2;

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Detailed Information

Recent Research

KDM5A (also known as RBP2 or JARID1A) is a member of the KDM5 protein family and is an H3K4 demethylase. In addition to the JmjC domain responsible for histone H3K4 demethylase activity, KDM5A also has two functional modules, the PHD finger and the ARID domain. A PHD finger of KDM5A has been shown to recognize H3K4me3 and plays a key role in leukemia when fused to other proteins such as nucleoporin 98. Furthermore, the ARID domain of KDM5A showed preferential DNA binding activity to the CCGCCC motif.

KDM5A was first identified as a factor that interacts with retinoblastoma gene product (RB) and has been shown to be involved in a variety of biological processes such as cell differentiation, senescence, tumorigenesis, circadian rhythm oscillations, and mitochondrial biogenesis. Studies have shown that KDM5A physically interacts with H3K9 methyltransferase G9a (a nuclear histone lysine methyltransferase) in mouse erythroid cells and synergistically inhibits the expression of embryonic globin genes. KDM5A homologous genes in Drosophila mutations cause differentiation and cell growth defects. Abnormal expression of genes is closely related to the development of human cancer. A number of reports have shown that KDM5A is highly expressed in gastric cancer, acute myeloid leukemia, ovarian cancer and breast cancer. KDM5A promotes EMT (epithelial-mesenchymal transition) and metastasis in ovarian cell lines. Furthermore, in estrogen receptor (ER) negative breast cancer, KDM5A mediates the spread of metastasis to the lungs.

KDM5A can directly target specific sites on chromatin and then recruit SIN3B-HDAC and NuRD complexes to integrate their enzymatic activities. Human KDM5A has been identified in the histone deacetylase (HDAC) 2 complex containing SIN3B, indicating that its demethylation activity is closely related to the histone deacetylation process. KDM5A is stably combined with two different HDAC complexes, namely HDAC and NuRD complexes containing SIN3B. The KDM5A and NuRD complexes act synergistically to control H3K4me3 levels associated with the target gene.

The histone demethylase KDM5A is a novel DDR (DNA Damage Response) factor that regulates ZMYND8-NuRD DDR activity. KDM5A was recruited for DNA damage, in which H3K4me3 was demethylated. Demethylation of H3K4me3 by KDM5A promotes the interaction between impaired chromatin and ZMYND8-NuRD, which contributes to the inhibition of active transcription and repair of DSB (Double strand break) by HR (homologous recombination). KDM5A acts upstream of ZMYND8-NuRD to promote its association with DNA damage and DDR activity in damaged chromatin, including inhibition of transcription and promotion of HR repair. The KDM5A-ZMYND8-NuRD DDR axis contains multiple chromatin interaction modules that form the molecular basis for identifying damaged chromatin. The recruitment of DNA damage by KDM5A is independent of ZMYND8-NuRD, but is dependent on PARP1 (pathway PolyADP-ribose-polymerase -1) signaling.

KDM5A is required for the initiation of NK (natural killer) cell activation by the inhibition of the inhibitory factor SOCS1 (cytokine signaling inhibitor 1). The H3K4me3 demethylase KDM5A regulates gene transcription and is involved in carcinogenesis. KDM5A lacks damage to natural killer (NK) cells and reduces IFN-g (interferon-gamma) production. Loss of KDM5A severely impairs phosphorylation and nuclear localization of STAT4 and increased expression of SOCS 1 during NK cell activation. Mechanistic studies indicate that KDM5A binds to p50 (A kind of NF-κB transcription factor) and binds to the Socs1 promoter region in resting NK cells, resulting in a significant decrease in H3K4me3 modification and inhibitory chromatin configuration at the Socs1 promoter.

References:

Horton J, et al. Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds. Cell Chemical Biology, 2016:S2451945616301945.
Gong F, et al. Histone demethylase KDM5A regulates the ZMYND8–NuRD chromatin remodeler to promote DNA repair. The Journal of Cell Biology, 2017:jcb.201611135.
Torres I O, et al. Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism. Nature Communications, 2015, 6:6204.
Shokri G, et al. Targeting histone demethylases KDM5A and KDM5B in AML cancer cells: A comparative view. Leukemia Research, 2018:S0145212618300316.
Zhao D, et al. H3K4me3 Demethylase Kdm5a Is Required for NK Cell Activation by Associating with p50 to Suppress SOCS1. Cell Reports, 2016:S2211124716302911.

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