Lan Fei, Shi Yang
Key Laboratory of Epigenetics of Shanghai Ministry of Education, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China; Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China;
Department of Cell Biology, Harvard Medical School, Boston, MA 02115; and Division of Newborn Medicine, Boston Children's Hospital, Boston MA 02115
Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):6814-9. doi: 10.1073/pnas.1418996111. Epub 2014 Dec 1.
The building block of chromatin is nucleosome, which consists of 146 base pairs of DNA wrapped around a histone octamer composed of two copies of histone H2A, H2B, H3, and H4. Significantly, the somatic missense mutations of the histone H3 variant, H3.3, are associated with childhood and young-adult tumors, such as pediatric high-grade astrocytomas, as well as chondroblastoma and giant-cell tumors of the bone. The mechanisms by which these histone mutations cause cancer are by and large unclear. Interestingly, two recent studies identified BS69/ZMYND11, which was proposed to be a candidate tumor suppressor, as a specific reader for a modified form of H3.3 (H3.3K36me3). Importantly, some H3.3 cancer mutations are predicted to abrogate the H3.3K36me3/BS69 interaction, suggesting that this interaction may play an important role in tumor suppression. These new findings also raise the question of whether H3.3 cancer mutations may lead to the disruption and/or gain of interactions of additional cellular factors that contribute to tumorigenesis.
染色质的基本组成单位是核小体，它由146个碱基对的DNA缠绕在一个组蛋白八聚体上组成，该八聚体由组蛋白H2A、H2B、H3和H4的两个拷贝构成。值得注意的是，组蛋白H3变体H3.3的体细胞错义突变与儿童期和青年期肿瘤相关，如儿童高级别星形细胞瘤，以及软骨母细胞瘤和骨巨细胞瘤。这些组蛋白突变导致癌症的机制目前大体上还不清楚。有趣的是，最近的两项研究确定了BS69/ZMYND11（被认为是一种候选肿瘤抑制因子）是修饰形式的H3.3（H3.3K36me3）的特异性识别蛋白。重要的是，一些H3.3癌症突变预计会消除H3.3K36me3/BS69的相互作用，这表明这种相互作用可能在肿瘤抑制中发挥重要作用。这些新发现也提出了一个问题，即H3.3癌症突变是否可能导致有助于肿瘤发生的其他细胞因子相互作用被破坏和/或获得。
