Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation.
Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation.
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DOI：
10.1074/jbc.m113.525279
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发表时间：
2014-03-21
期刊：
影响因子：
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通讯作者：
Pradhan S
中科院分区：
文献类型：
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作者：
Estève PO;Terragni J;Deepti K;Chin HG;Dai N;Espejo A;Corrêa IR Jr;Bedford MT;Pradhan S
背景：SET 7单甲基化DNMT 1，促进其蛋白酶体降解，但甲基化的DNMT 1仍然保留在整个细胞周期中。结果：甲基赖氨酸读取器PHF 20 L1稳定甲基化的DNMT 1。PHF 20 L1的破坏诱导DNMT 1降解和基因组低甲基化。结论：PHF 20 L1作为表观遗传阅读器，与书写器和擦除器协同调控表观遗传。意义：PHF 20 L1可以作为调节细胞中DNMT 1活性和DNA甲基化的手段。DNA胞嘧啶甲基化模式在连续细胞分裂期间的遗传由维持DNA（胞嘧啶-5）甲基转移酶1（DNMT 1）介导。DNMT 1的赖氨酸142被含有赖氨酸甲基转移酶7（SET 7）的SET结构域甲基化，导致其被蛋白酶体降解。在这里，我们表明，PHD指蛋白20样1（PHF 20 L1）调节哺乳动物细胞中的DNMT 1营业额。PHF 20 L1的恶性脑肿瘤（MBT）结构域与DNMT 1上的单甲基化赖氨酸142（DNMT 1 K142 me 1）结合，并以SET 7依赖性方式共定位于核仁周围空间。通过siRNA敲低PHF 20 L1导致染色质上DNMT 1的量减少。DNMT 1 K142 me 1的泛素化被PHF 20 L1的过表达所消除，这表明PHF 20 L1的结合可以阻断DNMT 1 K142 me 1的蛋白酶体降解。相反，siRNA介导的PHF 20 L1敲低或在培养细胞中孵育小分子MBT结构域结合抑制剂加速了DNMT 1的蛋白酶体降解。这些结果表明，PHF 20 L1的MBT结构域读取并控制细胞中甲基化DNMT 1的酶水平，因此代表DNMT 1降解的新型拮抗剂。
Background: SET7 monomethylates DNMT1, promoting its proteasomal degradation, yet methylated DNMT1 still remains throughout the cell cycle. Results: The methyllysine reader PHF20L1 stabilizes methylated DNMT1. Disruption of PHF20L1 induces DNMT1 degradation and genome hypomethylation. Conclusion: PHF20L1, an epigenetic reader, cooperates with writer and eraser to regulate epigenetic inheritance. Significance: PHF20L1 can be targeted as a means of regulating DNMT1 activity and DNA methylation in cells. Inheritance of DNA cytosine methylation pattern during successive cell division is mediated by maintenance DNA (cytosine-5) methyltransferase 1 (DNMT1). Lysine 142 of DNMT1 is methylated by the SET domain containing lysine methyltransferase 7 (SET7), leading to its degradation by proteasome. Here we show that PHD finger protein 20-like 1 (PHF20L1) regulates DNMT1 turnover in mammalian cells. Malignant brain tumor (MBT) domain of PHF20L1 binds to monomethylated lysine 142 on DNMT1 (DNMT1K142me1) and colocalizes at the perinucleolar space in a SET7-dependent manner. PHF20L1 knockdown by siRNA resulted in decreased amounts of DNMT1 on chromatin. Ubiquitination of DNMT1K142me1 was abolished by overexpression of PHF20L1, suggesting that its binding may block proteasomal degradation of DNMT1K142me1. Conversely, siRNA-mediated knockdown of PHF20L1 or incubation of a small molecule MBT domain binding inhibitor in cultured cells accelerated the proteasomal degradation of DNMT1. These results demonstrate that the MBT domain of PHF20L1 reads and controls enzyme levels of methylated DNMT1 in cells, thus representing a novel antagonist of DNMT1 degradation.