The acetyltransferase Tip60 contributes to mammary tumorigenesis by modulating DNA repair.
The acetyltransferase Tip60 contributes to mammary tumorigenesis by modulating DNA repair.
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DOI：
10.1038/cdd.2015.173
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发表时间：
2016-07
影响因子：
12.4
通讯作者：
Gorrini C
中科院分区：
文献类型：
--
作者：
Bassi C;Li YT;Khu K;Mateo F;Baniasadi PS;Elia A;Mason J;Stambolic V;Pujana MA;Mak TW;Gorrini C
乙酰转移酶Tip 60/Kat 5乙酰化组蛋白和非组蛋白蛋白，并参与各种生物过程。通过乙酰化p53，Tip 60控制p53依赖性转录活性，因此被认为是肿瘤抑制因子。然而，许多低Tip 60的乳腺癌也显示p53突变，这意味着Tip 60具有不依赖于其p53乙酰化的肿瘤抑制功能。在这里，我们在散发性侵袭性乳腺癌的p53缺失小鼠模型中表明，Tip 60缺失的杂合性促进了乳腺肿瘤的发生。低Tip 60减少正常和肿瘤乳腺上皮细胞的DNA修复，无论是在静息条件下还是在遗传毒性应激后。我们证明，Tip 60控制同源重组（HR）指导的DNA修复，Tip 60水平与有缺陷的HR指导的DNA修复相关的基因表达特征呈负相关。在人类乳腺癌数据集中，Tip 60 mRNA下调，低Tip 60水平与基底样乳腺癌中的p53突变相关。我们的研究结果表明，Tip 60是一种新的乳腺肿瘤抑制基因，其丢失导致基因组不稳定，导致癌症形成。
The acetyltransferase Tip60/Kat5 acetylates both histone and non-histone proteins, and is involved in a variety of biological processes. By acetylating p53, Tip60 controls p53-dependent transcriptional activity and so is implicated as a tumor suppressor. However, many breast cancers with low Tip60 also show p53 mutation, implying that Tip60 has a tumor suppressor function independent of its acetylation of p53. Here, we show in a p53-null mouse model of sporadic invasive breast adenocarcinoma that heterozygosity for Tip60 deletion promotes mammary tumorigenesis. Low Tip60 reduces DNA repair in normal and tumor mammary epithelial cells, both under resting conditions and following genotoxic stress. We demonstrate that Tip60 controls homologous recombination (HR)-directed DNA repair, and that Tip60 levels correlate inversely with a gene expression signature associated with defective HR-directed DNA repair. In human breast cancer data sets, Tip60 mRNA is downregulated, with low Tip60 levels correlating with p53 mutations in basal-like breast cancers. Our findings indicate that Tip60 is a novel breast tumor suppressor gene whose loss results in genomic instability leading to cancer formation.