Chromatin Sensing by the Auxiliary Domains of KDM5C Regulates Its Demethylase Activity and Is Disrupted by X-linked Intellectual Disability Mutations.
Chromatin Sensing by the Auxiliary Domains of KDM5C Regulates Its Demethylase Activity and Is Disrupted by X-linked Intellectual Disability Mutations.
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DOI：
10.1016/j.jmb.2022.167913
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发表时间：
2023-01-30
影响因子：
5.6
通讯作者：
Fujimori, Danica Galonic
中科院分区：
文献类型：
--
作者：
Ugur, Fatima S.;Kelly, Mark J. S.;Fujimori, Danica Galonic
H3K4me3染色质修饰是活跃转录基因启动子的标志，被组蛋白去甲基酶KDM5家族动态移除。KDM5去甲基酶具有多个辅助结构域，其中两个辅助结构域位于催化结构域之间，分别为isd和Phd1。KDM5C在神经发育中具有独特的作用，其附属结构域附近存在许多突变，导致X连锁智力残疾(XLID)。这些辅助结构域的作用尚不清楚，限制了对XLID突变如何影响KDM5C活性的理解。通过使用核小体的体外结合和动力学研究，我们发现，虽然干旱结构域是有效的核小体去甲基化所必需的，但仅PhD1结构域在KDM5C催化中具有抑制作用。此外，ARID和PhD1结构域之间的非结构化连接区与PhD1相互作用，是核小体结合所必需的。我们的数据提出了一种模型，在该模型中，PhD1结构域抑制了KDM5C对DNA的识别。这种抑制作用被H3尾巴解除，使核小体上的侧翼DNA能够识别。重要的是，我们发现靠近ARID和PhD1结构域的XLID突变通过增强DNA结合来打破这一调节，导致底物染色质识别的特异性丧失，并在侧翼DNA存在的情况下使去甲基酶活性降低。我们的发现提出了一种模型，通过该模型，特定的XLID突变可以改变染色质识别，并使KDM5C对常染色质特异性去甲基化的失调能够实现。
The H3K4me3 chromatin modification, a hallmark of promoters of actively transcribed genes, is dynamically removed by the KDM5 family of histone demethylases. The KDM5 demethylases have a number of accessory domains, two of which, ARID and PHD1, lie between the segments of the catalytic domain. KDM5C, which has a unique role in neural development, harbors a number of mutations adjacent to its accessory domains that cause X-linked intellectual disability (XLID). The roles of these accessory domains remain unknown, limiting an understanding of how XLID mutations affect KDM5C activity. Through in vitro binding and kinetic studies using nucleosomes, we find that while the ARID domain is required for efficient nucleosome demethylation, the PHD1 domain alone has an inhibitory role in KDM5C catalysis. In addition, the unstructured linker region between the ARID and PHD1 domains interacts with PHD1 and is necessary for nucleosome binding. Our data suggests a model in which the PHD1 domain inhibits DNA recognition by KDM5C. This inhibitory effect is relieved by the H3 tail, enabling recognition of flanking DNA on the nucleosome. Importantly, we find that XLID mutations adjacent to the ARID and PHD1 domains break this regulation by enhancing DNA binding, resulting in the loss of specificity of substrate chromatin recognition and rendering demethylase activity lower in the presence of flanking DNA. Our findings suggest a model by which specific XLID mutations could alter chromatin recognition and enable euchromatin-specific dysregulation of demethylation by KDM5C.
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影响因子：
16.6
作者：
Gatchalian J;Wang X;Ikebe J;Cox KL;Tencer AH;Zhang Y;Burge NL;Di L;Gibson MD;Musselman CA;Poirier MG;Kono H;Hayes JJ;Kutateladze TG
通讯作者：
Kutateladze TG
影响因子：
5.8
作者：
Hatazawa, Suguru;Liu, Jiuyang;Takizawa, Yoshimasa;Zandian, Mohamad;Negishi, Lumi;Kutateladze, Tatiana G.;Kurumizaka, Hitoshi
通讯作者：
Kurumizaka, Hitoshi
影响因子：
7.7
作者：
Keenen MM;Brown D;Brennan LD;Renger R;Khoo H;Carlson CR;Huang B;Grill SW;Narlikar GJ;Redding S
通讯作者：
Redding S
影响因子：
16
作者：
Blackledge NP;Zhou JC;Tolstorukov MY;Farcas AM;Park PJ;Klose RJ
通讯作者：
Klose RJ
DOI：
10.1186/1755-8417-3-2
发表时间：
2010-02-02
期刊：
PathoGenetics
影响因子：
--
作者：
Jensen, Lars R;Bartenschlager, Heinz;Kuss, Andreas W
通讯作者：
Kuss, Andreas W