Inhibition of histone H3-H4 chaperone pathways rescues C. elegans sterility by H2B loss.
Inhibition of histone H3-H4 chaperone pathways rescues C. elegans sterility by H2B loss.
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抑制组蛋白 H3-H4 伴侣通路可通过 H2B 损失挽救线虫不育性
DOI：
10.1371/journal.pgen.1010223
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发表时间：
2022-06
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
癌组蛋白突变是肿瘤发生的关键驱动因素，但生物体如何控制癌组蛋白功能丧失仍不清楚。我们在秀丽隐杆线虫中产生了组蛋白H2B三敲除（3KO）菌株，该菌株降低了胚胎H2B，破坏了细胞分裂，并导致动物不育。通过进行基因抑制筛选，我们发现组蛋白H3-H4伴侣UNC-85突变缺陷通过降低染色质H3-H4水平来恢复H2B 3KO的生育能力。其他H3-H4伴侣或H3或H4组蛋白的RNA干扰也能挽救H2B 3KO不育。我们发现，阻断H3-H4伴侣蛋白可以恢复携带嗜糖组蛋白H2BE74K突变的秀丽隐杆线虫的细胞分裂，该突变会扭曲H2B-H4界面并诱导核小体不稳定。我们的研究结果表明，减少H3-H4染色质可以在体内拯救功能失调的H2B，并提示抑制H3-H4伴侣可能为治疗由H2B肿瘤组蛋白功能丧失引起的癌症提供有效的治疗策略。功能失调的组蛋白导致发育缺陷并驱动肿瘤发生。利用秀丽隐杆线虫研究组蛋白H2B缺失，我们发现抑制组蛋白H3-H4伴侣通过降低染色质H3-H4水平恢复H2B三敲除的生育能力。H3-H4伴侣的阻断恢复了携带嗜糖组蛋白H2BE74K突变的秀丽隐杆线虫的细胞分裂，该突变扭曲了H2B-H4界面并诱导核小体不稳定。我们认为，核小体中组蛋白的总体化学计量比组蛋白二聚体或四聚体的实际丰度更重要，抑制H3-H4伴侣蛋白可能为治疗由H2B组蛋白功能丧失引起的癌症提供有效的治疗策略。
Oncohistone mutations are crucial drivers for tumorigenesis, but how a living organism governs the loss-of-function oncohistone remains unclear. We generated a histone H2B triple knockout (3KO) strain in Caenorhabditis elegans, which decreased the embryonic H2B, disrupted cell divisions, and caused animal sterility. By performing genetic suppressor screens, we uncovered that mutations defective in the histone H3-H4 chaperone UNC-85 restored H2B 3KO fertility by decreasing chromatin H3-H4 levels. RNA interference of other H3-H4 chaperones or H3 or H4 histones also rescued H2B 3KO sterility. We showed that blocking H3-H4 chaperones recovered cell division in C. elegans carrying the oncohistone H2BE74K mutation that distorts the H2B-H4 interface and induces nucleosome instability. Our results indicate that reducing chromatin H3-H4 rescues the dysfunctional H2B in vivo and suggest that inhibiting H3-H4 chaperones may provide an effective therapeutic strategy for treating cancers resulting from loss-of-function H2B oncohistone. Dysfunctional histones cause developmental defects and drive tumorigenesis. Using Caenorhabditis elegans to study histone H2B loss, we found that inhibiting histone H3-H4 chaperones restored fertility in H2B triple knockouts by decreasing chromatin H3-H4 levels. The blockade of H3-H4 chaperones recovered cell division in C. elegans carrying the oncohistone H2BE74K mutation that distorts the H2B-H4 interface and induces nucleosome instability. We suggest that the overall stoichiometry of histones within nucleosomes is more important than the actual abundances of histone dimers or tetramers and that inhibiting H3-H4 chaperones may provide an effective therapeutic strategy for treating cancers resulting from loss-of-function H2B oncohistone.
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影响因子：
14.9
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
通讯作者：
Kurumizaka H
DOI：
10.1534/g3.115.026815
发表时间：
2016-04-07
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Huelgas-Morales G;Silva-García CG;Salinas LS;Greenstein D;Navarro RE
通讯作者：
Navarro RE
影响因子：
16.6
作者：
Delaney, Kamila;Strobino, Maude;Steiner, Florian A.
通讯作者：
Steiner, Florian A.
DOI：
10.1038/nrm.2016.159
发表时间：
2017-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Hammond CM;Strømme CB;Huang H;Patel DJ;Groth A
通讯作者：
Groth A
影响因子：
64.8
作者：
Kaletsky R;Moore RS;Vrla GD;Parsons LR;Gitai Z;Murphy CT
通讯作者：
Murphy CT