Kdm5a, also named RBP2 or JARID1A, is a lysine-specific demethylase. It can remove methyl groups from histones H3K4me1/2/3, and is involved in regulating chromatin-related activities such as transcriptional regulation and epigenetic inheritance [1,2]. It plays a role in multiple cellular processes including differentiation, metabolism, cell cycle, and transcription [3].

Kdm5a has been found to be aberrantly expressed in many cancers, contributing to cancer cell proliferation, metastasis, invasiveness, drug resistance, and is associated with poor prognosis. Pharmacological inhibition of Kdm5A significantly attenuates tumor progression in vitro and in vivo in solid tumors and acute myeloid leukemia [1]. In addition, Kdm5A/B contribute to HIV-1 latent infection and survival of HIV-1 infected cells, and KDM5A and KDM5B histone-demethylases contribute to replication stress response and tolerance [4,5]. Kdm5a knockout mouse model showed that inactivating Kdm5a disrupts vocalization, and these mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis [6]. The NUP98-KDM5A chimeric protein in pediatric AML patients generates genomic instability through two complementary mechanisms [7].

In conclusion, Kdm5a is a crucial histone demethylase with a significant impact on multiple biological processes. Model-based research, especially the Kdm5a knockout mouse model, has revealed its important roles in various diseases such as cancer, HIV-1 infection, and autism spectrum disorder, as well as in replication stress response. Understanding Kdm5a provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Yang, Guan-Jun, Wu, Jia, Miao, Liang, Ma, Dik-Lung, Chen, Jiong. 2021. Pharmacological inhibition of KDM5A for cancer treatment. In European journal of medicinal chemistry, 226, 113855. doi:10.1016/j.ejmech.2021.113855. https://pubmed.ncbi.nlm.nih.gov/34555614/

2. Yang, Guan-Jun, Zhu, Ming-Hui, Lu, Xin-Jiang, Ma, Dik-Lung, Chen, Jiong. 2021. The emerging role of KDM5A in human cancer. In Journal of hematology & oncology, 14, 30. doi:10.1186/s13045-021-01041-1. https://pubmed.ncbi.nlm.nih.gov/33596982/

3. Kataria, Avishek, Tyagi, Shweta. 2023. Domain architecture and protein-protein interactions regulate KDM5A recruitment to the chromatin. In Epigenetics, 18, 2268813. doi:10.1080/15592294.2023.2268813. https://pubmed.ncbi.nlm.nih.gov/37838974/

4. Li, Tai-Wei, Park, Youngmin, Watters, Emily G, Qi, Jun, Zhu, Jian. 2024. KDM5A/B contribute to HIV-1 latent infection and survival of HIV-1 infected cells. In Antiviral research, 228, 105947. doi:10.1016/j.antiviral.2024.105947. https://pubmed.ncbi.nlm.nih.gov/38925368/

5. Gaillard, Solenne, Charasson, Virginie, Ribeyre, Cyril, Trouche, Didier, Vandromme, Marie. 2021. KDM5A and KDM5B histone-demethylases contribute to HU-induced replication stress response and tolerance. In Biology open, 10, . doi:10.1242/bio.057729. https://pubmed.ncbi.nlm.nih.gov/34184733/

6. El Hayek, Lauretta, Tuncay, Islam Oguz, Nijem, Nadine, Beutler, Bruce, Chahrour, Maria H. 2020. KDM5A mutations identified in autism spectrum disorder using forward genetics. In eLife, 9, . doi:10.7554/eLife.56883. https://pubmed.ncbi.nlm.nih.gov/33350388/

7. Domingo-Reinés, Joan, Montes, Rosa, Garcia-Moreno, Adrián, Landeira, David, Ramos-Mejia, Verónica. 2023. The pediatric leukemia oncoprotein NUP98-KDM5A induces genomic instability that may facilitate malignant transformation. In Cell death & disease, 14, 357. doi:10.1038/s41419-023-05870-5. https://pubmed.ncbi.nlm.nih.gov/37301844/