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Nature :突变体p53与组蛋白甲基化的关系

2015-10-08 14:06  
内容快照:

Nature :突变体p53与组蛋白甲基化的关系

野生型p53是一个肿瘤抑制因子,但p53的突变会促进癌症,而且某些致癌形式还是“功能获得”(GOF)型突变体。Shelley Berger及同事利用ChIP-seq分析比较了野生型和“功能获得”型突变体p53的基因组结合模式,发现p53突变体与野生型蛋白相比所结合的基因类型截然不同,其中关键目标包括组蛋白甲基转移酶MLL1和MLL2以及其他染色质修饰酶。“功能获得”型p53突变体细胞高度依靠MLL通道来生长,并且对MLL功能的小分子抑制剂是敏感的,从而为携带这些p53突变的癌症指出了一条新的治疗途径。

原文链接:

Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth

原文摘要:

TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a ‘gain-of-function’ (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2(also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.

Figure 1: Genome-wide binding of GOF p53 mutants.

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