The PR-Set7 binding domain of Riz1 is required for the H4K20me1-H3K9me1 trans-tail 'histone code' and Riz1 tumor suppressor function.
The PR-Set7 binding domain of Riz1 is required for the H4K20me1-H3K9me1 trans-tail 'histone code' and Riz1 tumor suppressor function.
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DOI：
10.1093/nar/gkt1377
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发表时间：
2014-04
影响因子：
14.9
通讯作者：
Rice JC
中科院分区：
文献类型：
--
作者：
Congdon LM;Sims JK;Tuzon CT;Rice JC
PR-Set7/Set8/KMT5a是后生动物中唯一的组蛋白H4赖氨酸20单甲基转移酶(H4K20me1)，对细胞的正常分裂和基因组的稳定是必不可少的。我们意外地发现，正常细胞水平的单甲基化组蛋白H3赖氨酸9(H3K9me1)也依赖于PR-Set7，但与其催化活性无关。这一观察结果表明，PR-Set7与H3K9单甲基转移酶相互作用，建立了先前报道的H4K20me1-H3K9me1反式尾‘组蛋白密码’。在这里，我们证明了PR-Set7特异性地直接与Riz1/PRDM2/KMT8抑癌基因的C末端结合，并证明Riz1的N端PR/SET结构域优先与H3K9单甲基化。PR-Set7结合域是Riz1核定位和维持H4K20me1-H3K9me1反式尾‘组蛋白密码’所必需的。虽然Riz1可以作为抑制子发挥作用，但Riz1/H3K9me1对于PR-Set7/H4K20me1调控基因的抑制是必不可少的。移码突变导致截短的Riz1不能结合PR-Set7，在各种侵袭性癌症中经常发生。在这些癌细胞中，野生型Riz1的表达通过抑制增殖和增加凋亡来恢复对肿瘤的抑制。这些表型在表达Riz1 PR/SET结构域和PR-Set7结合域的细胞中均未观察到，表明Riz1甲基转移酶活性和PR-Set7结合域都是Riz1抑癌功能所必需的。
PR-Set7/Set8/KMT5a is the sole histone H4 lysine 20 monomethyltransferase (H4K20me1) in metazoans and is essential for proper cell division and genomic stability. We unexpectedly discovered that normal cellular levels of monomethylated histone H3 lysine 9 (H3K9me1) were also dependent on PR-Set7, but independent of its catalytic activity. This observation suggested that PR-Set7 interacts with an H3K9 monomethyltransferase to establish the previously reported H4K20me1-H3K9me1 trans-tail ‘histone code’. Here we show that PR-Set7 specifically and directly binds the C-terminus of the Riz1/PRDM2/KMT8 tumor suppressor and demonstrate that the N-terminal PR/SET domain of Riz1 preferentially monomethylates H3K9. The PR-Set7 binding domain was required for Riz1 nuclear localization and maintenance of the H4K20me1-H3K9me1 trans-tail ‘histone code’. Although Riz1 can function as a repressor, Riz1/H3K9me1 was dispensable for the repression of genes regulated by PR-Set7/H4K20me1. Frameshift mutations resulting in a truncated Riz1 incapable of binding PR-Set7 occur frequently in various aggressive cancers. In these cancer cells, expression of wild-type Riz1 restored tumor suppression by decreasing proliferation and increasing apoptosis. These phenotypes were not observed in cells expressing either the Riz1 PR/SET domain or PR-Set7 binding domain indicating that Riz1 methyltransferase activity and PR-Set7 binding domain are both essential for Riz1 tumor suppressor function.
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影响因子：
4.8
作者：
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