Palla Ali M, Lin Chien-Chu, Trnka Michael J, Leao Emme M, Petronikolou Nektaria, Burlingame Alma L, McGinty Robert K, Fujimori Danica Galonić
TETRAD Graduate Program, University of California, 600 16th Street, Genentech Hall, San Francisco, CA, 94158, USA.
Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, Chapel Hill, NC, 27599 USA.
bioRxiv. 2025 May 2:2025.05.01.651538. doi: 10.1101/2025.05.01.651538.
Lysine demethylase 5A (KDM5A) plays a key role in the regulation of chromatin accessibility by catalyzing the removal of trimethyl marks on histone H3K4 (H3K4me3). KDM5A is also an oncogenic driver, with overexpression of KDM5A observed in various cancers, including breast, lung, and ovarian cancer. Past studies have characterized the functions of KDM5A domains, including KDM5A interactions with the histone H3 tail, but have yet to identify the broader mechanisms that drive KDM5A binding to the nucleosome. Through investigation of binding and catalysis on nucleosome substrates, we uncovered multivalent interactions of KDM5A with the H2A/H2B acidic patch and DNA that play crucial roles in the regulation of catalytic activity. We also identified an intrinsically disordered region (IDR) containing bifunctional arginine-rich motifs capable of binding to both the histone H2A/H2B acidic patch and nucleosomal DNA that is necessary for catalysis on nucleosome substrates. Our findings both elucidate previously unknown mechanisms that regulate KDM5A catalytic activity and reveal the ability of an IDR to engage in multiple interactions with chromatin.
赖氨酸去甲基化酶5A（KDM5A）通过催化去除组蛋白H3K4上的三甲基标记（H3K4me3），在染色质可及性的调节中起关键作用。KDM5A也是一种致癌驱动因子，在包括乳腺癌、肺癌和卵巢癌在内的多种癌症中均观察到KDM5A的过表达。过去的研究已经描述了KDM5A结构域的功能，包括KDM5A与组蛋白H3尾部的相互作用，但尚未确定驱动KDM5A与核小体结合的更广泛机制。通过对核小体底物上的结合和催化作用进行研究，我们发现了KDM5A与H2A/H2B酸性补丁和DNA的多价相互作用，这些相互作用在催化活性的调节中起着关键作用。我们还鉴定了一个包含双功能富含精氨酸基序的内在无序区域（IDR），该区域能够与组蛋白H2A/H2B酸性补丁和核小体DNA结合，这是核小体底物催化所必需的。我们的研究结果既阐明了调节KDM5A催化活性的先前未知机制，又揭示了一个IDR与染色质进行多种相互作用的能力。
