Chd5 requires PHD-mediated histone 3 binding for tumor suppression.
Chd5 requires PHD-mediated histone 3 binding for tumor suppression.
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DOI：
10.1016/j.celrep.2012.12.009
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发表时间：
2013-01-31
期刊：
影响因子：
8.8
通讯作者：
Mills AA
中科院分区：
文献类型：
--
作者：
Paul S;Kuo A;Schalch T;Vogel H;Joshua-Tor L;McCombie WR;Gozani O;Hammell M;Mills AA
染色质解旋酶dna结合蛋白5 （CHD5）是一个定位于人类癌症中经常缺失的基因组区域1p36的肿瘤抑制因子。虽然CHD5属于冠心病家族的染色质重塑蛋白，但其肿瘤抑制作用是否涉及与染色质的相互作用尚不清楚。在这里，我们报道Chd5通过其串联植物同源结构域（PHDs）结合H3的未修饰n端。全基因组ChIP研究揭示了Chd5与缺乏活性标记H3K4me3的位点的优先结合，并发现了与癌症有关的新的Chd5靶点。取消H3结合的Chd5突变不能抑制增殖或转录调节靶基因，导致体内肿瘤发生。与野生型Chd5不同，Chd5- phd突变体在体内不能诱导分化或有效抑制人神经母细胞瘤的生长。我们的工作将Chd5定义为n端未修饰的h3结合蛋白，并提供了功能证据，证明这种相互作用协调了染色质介导的转录程序，对肿瘤抑制至关重要。
ChromodomainHelicase DNA-binding protein 5 (CHD5) is a tumor suppressor mapping to 1p36—a genomic region frequently deleted in human cancer. Although CHD5 belongs to the CHD family of chromatin remodeling proteins, whether its tumor suppressive role involves an interaction with chromatin is unknown. Here we report that Chd5 binds the unmodified N-terminus of H3 through its tandem plant homeodomains (PHDs). Genome-wide ChIP studies reveal preferential binding of Chd5 to loci lacking the active mark H3K4me3, and also identify novel Chd5-targets implicated in cancer. Chd5 mutations abrogating H3 binding are unable to inhibit proliferation or to transcriptionally modulate target genes, leading to tumorigenesis in vivo. Unlike wild-type Chd5, Chd5-PHD mutants are unable to induce differentiation or to efficiently suppress growth of human neuroblastoma in vivo. Our work defines Chd5 as an N-terminally unmodified H3-binding protein and provides functional evidence that this interaction orchestrates chromatin-mediated transcriptional programs critical for tumor suppression.
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影响因子：
37.3
作者：
Garcia I;Mayol G;Rodríguez E;Suñol M;Gershon TR;Ríos J;Cheung NK;Kieran MW;George RE;Perez-Atayde AR;Casala C;Galván P;de Torres C;Mora J;Lavarino C
通讯作者：
Lavarino C
DOI：
10.1158/1078-0432.ccr-11-2483
发表时间：
2012-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Garcia I;Mayol G;Ríos J;Domenech G;Cheung NK;Oberthuer A;Fischer M;Maris JM;Brodeur GM;Hero B;Rodríguez E;Suñol M;Galvan P;de Torres C;Mora J;Lavarino C
通讯作者：
Lavarino C
影响因子：
10.3
作者：
Lang, J.;Tobias, E. S.;MacKie, R.
通讯作者：
MacKie, R.
影响因子：
64.5
作者：
Bagchi, Anindya;Papazoglu, Cristian;Mills, Alea A.
通讯作者：
Mills, Alea A.
影响因子：
64.8
作者：
Berger, Michael F.;Lawrence, Michael S.;Demichelis, Francesca;Drier, Yotam;Cibulskis, Kristian;Sivachenko, Andrey Y.;Sboner, Andrea;Esgueva, Raquel;Pflueger, Dorothee;Sougnez, Carrie;Onofrio, Robert;Carter, Scott L.;Park, Kyung;Habegger, Lukas;Ambrogio, Lauren;Fennell, Timothy;Parkin, Melissa;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Pugh, Trevor J.;Wilkinson, Jane;Fisher, Sheila;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Simons, Jonathan W.;Kitabayashi, Naoki;MacDonald, Theresa Y.;Kantoff, Philip W.;Chin, Lynda;Gabriel, Stacey B.;Gerstein, Mark B.;Golub, Todd R.;Meyerson, Matthew;Tewari, Ashutosh;Lander, Eric S.;Getz, Gad;Rubin, Mark A.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.