Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome.
Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome.
复制标题
DOI：
10.1093/nar/gky661
复制
发表时间：
2018-11-02
影响因子：
14.9
通讯作者：
Kurumizaka H
中科院分区：
文献类型：
--
作者：
Arimura Y;Ikura M;Fujita R;Noda M;Kobayashi W;Horikoshi N;Sun J;Shi L;Kusakabe M;Harata M;Ohkawa Y;Tashiro S;Kimura H;Ikura T;Kurumizaka H
典型组蛋白H2B的Glu76残基的突变经常在癌细胞中发现。然而，多个H2B基因之一的单个氨基酸取代如何影响细胞命运是相当神秘的。在这里，我们发现，H2B E76K突变，其中Glu76被替换为Lys（E76K），扭曲了核小体中H2B和H4之间的界面，如晶体结构所示，并在体内和体外诱导核小体不稳定。外源产生的H2B E76 K突变体强烈增强了表达细胞的殖民地形成能力，表明H2B E76 K突变体在野生型H2B存在下具有促进致癌转化的潜力。我们发现组蛋白的其他癌症相关突变H3.1 E97 K和H2A.Z.1 R80 C也诱导核小体不稳定性。有趣的是，与H2 B E76 K突变体一样，H3.1 E97 K突变体最低限度地掺入细胞中的染色质中，但它增强了殖民地形成能力。相反，H2A.Z.1 R80 C突变体掺入细胞的染色质中，并且对细胞的殖民地形成能力具有较小的影响。具有癌症相关突变的组蛋白的这些特征可能为理解突变如何促进癌症进展提供重要信息。
Mutations of the Glu76 residue of canonical histone H2B are frequently found in cancer cells. However, it is quite mysterious how a single amino acid substitution in one of the multiple H2B genes affects cell fate. Here we found that the H2B E76K mutation, in which Glu76 is replaced by Lys (E76K), distorted the interface between H2B and H4 in the nucleosome, as revealed by the crystal structure and induced nucleosome instability in vivo and in vitro. Exogenous production of the H2B E76K mutant robustly enhanced the colony formation ability of the expressing cells, indicating that the H2B E76K mutant has the potential to promote oncogenic transformation in the presence of wild-type H2B. We found that other cancer-associated mutations of histones, H3.1 E97K and H2A.Z.1 R80C, also induced nucleosome instability. Interestingly, like the H2B E76K mutant, the H3.1 E97K mutant was minimally incorporated into chromatin in cells, but it enhanced the colony formation ability. In contrast, the H2A.Z.1 R80C mutant was incorporated into chromatin in cells, and had minor effects on the colony formation ability of the cells. These characteristics of histones with cancer-associated mutations may provide important information toward understanding how the mutations promote cancer progression.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1083/jcb.153.7.1341
发表时间：
2001-06-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kimura H;Cook PR
通讯作者：
Cook PR
影响因子：
14.9
作者：
Kujirai T;Horikoshi N;Sato K;Maehara K;Machida S;Osakabe A;Kimura H;Ohkawa Y;Kurumizaka H
通讯作者：
Kurumizaka H
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH