Histone Deacetylase 1 Inhibition by Peptides Containing a DNA Damage-Induced, Nonenzymatic, Histone Covalent Modification.
Histone Deacetylase 1 Inhibition by Peptides Containing a DNA Damage-Induced, Nonenzymatic, Histone Covalent Modification.
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DOI：
10.1021/acs.biochem.3c00007
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发表时间：
2023-03
期刊：
影响因子：
2.9
通讯作者：
Marco Paolo Jacinto;M. Greenberg
中科院分区：
文献类型：
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作者：
Marco Paolo Jacinto;M. Greenberg
用 DNA 损伤剂博莱霉素 (BLM) 处理 HeLa 细胞，会在赖氨酸残基 (KMP) 上形成非酶促 5-亚甲基-2-吡咯酮组蛋白共价修饰。 KMP 比其他 N-酰基赖氨酸共价修饰和翻译后修饰（包括 N-乙酰赖氨酸 (KAc)）更具亲电性。使用含有 KMP 的组蛋白肽，我们发现这种修饰通过与位于活性位点附近的保守半胱氨酸 (C261) 反应来抑制 I 类组蛋白脱乙酰酶 HDAC1。 HDAC1 受到组蛋白肽的抑制，组蛋白肽的相应 N-乙酰化序列是已知的脱乙酰化底物，但不包含乱序序列。 HDAC1 抑制剂曲古抑菌素 A 与含 KMP 的肽的共价修饰竞争。 HDAC1 也会在复杂的环境中被含 KMP 的肽共价修饰。这些数据表明含有 KMP 的肽被 HDAC1 识别并结合在活性位点。对 HDAC1 的影响表明细胞中 KMP 的形成可能有助于形成这种非酶共价修饰的 DNA 损伤剂（例如 BLM）的生物效应。
Treatment of HeLa cells with the DNA damaging agent, bleomycin (BLM), results in the formation of a nonenzymatic 5-methylene-2-pyrrolone histone covalent modification on lysine residues (KMP). KMP is much more electrophilic than other N-acyllysine covalent modifications and post-translational modifications, including N-acetyllysine (KAc). Using histone peptides containing KMP, we show that this modification inhibits the class I histone deacetylase, HDAC1, by reacting with a conserved cysteine (C261) located near the active site. HDAC1 is inhibited by histone peptides whose corresponding N-acetylated sequences are known deacetylation substrates, but not one containing a scrambled sequence. The HDAC1 inhibitor, trichostatin A, competes with covalent modification by the KMP-containing peptides. HDAC1 is also covalently modified by a KMP-containing peptide in a complex milieu. These data indicate that peptides containing KMP are recognized by HDAC1 and are bound in the active site. The effects on HDAC1 indicate that KMP formation in cells may contribute to the biological effects of DNA damaging agents, such as BLM, that form this nonenzymatic covalent modification.