KDM5A

KDM5A Full Name

lysine (K)-specific demethylase 5A

KDM5A Introduction

KDM5A (also known as JARID1A or RBP2) is a JmjC-domain histone demethylase that selectively removes H3K4me2 and H3K4me3, two activating chromatin marks associated with active promoters and enhancers. By erasing these marks, KDM5A generally dampens transcription of its target genes. The protein is recruited to chromatin through its PHD fingers, which read unmodified or methylated histone tails, and through interactions with transcription factors such as REST, Myc, and the nuclear receptors. The KDM5A gene maps to chromosome 12p13.33, a region frequently deleted or amplified in cancer.

Figure 1. (The human jrkl (jerky-like) gene & protein: structure, conservation,and predicted functions.

Erasure of H3K4me3 and Transcriptional Repression
KDM5A demethylates H3K4me3 at promoters and super-enhancers, creating a chromatin environment that resists productive transcription initiation. At Myc-responsive genes, KDM5A directly antagonizes Myc-driven transcriptional amplification, restricting expression to a defined dynamic range. KDM5A also partners with the transcriptional repressor REST to silence neuronal genes in non-neuronal cells, and with the androgen receptor to modulate proliferation in prostate cancer cells. In addition, KDM5A has been reported to bind the p107 and p130 pocket proteins, suggesting integration with the retinoblastoma tumor-suppressor pathway.

Drug-Resistant Cancers and Developmental Disorders
KDM5A is overexpressed in several drug-resistant cancers, including tamoxifen-resistant breast cancer and chemorefractory lung adenocarcinoma, where its activity dampens lineage-specifying transcription programs and enables survival under therapeutic pressure. Pharmacological inhibitors of KDM5 family demethylases are in early clinical development as adjuncts to reverse drug resistance. Heterozygous deletions spanning KDM5A and the neighboring gene ETV6 produce a contiguous-gene syndrome associated with developmental delay and hematologic abnormalities, and rare KDM5A point mutations have been reported in patients with syndromic intellectual disability.

Alternate Names for KDM5A

KDM5A; lysine (K)-specific demethylase 5A; RBP2; RBBP2; RBBP-2; lysine-specific demethylase 5A; histone demethylase JARID1A; retinoblastoma binding protein 2; jumonji/ARID domain-containing protein 1A; Jumonji, AT rich interactive domain 1A (RBP2-like);