CHK1-driven histone H3.3 serine 31 phosphorylation is important for chromatin maintenance and cell survival in human ALT cancer cells.
CHK1-driven histone H3.3 serine 31 phosphorylation is important for chromatin maintenance and cell survival in human ALT cancer cells.
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DOI：
10.1093/nar/gkv104
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发表时间：
2015-03-11
影响因子：
14.9
通讯作者：
Wong LH
中科院分区：
文献类型：
--
作者：
Chang FT;Chan FL;R McGhie JD;Udugama M;Mayne L;Collas P;Mann JR;Wong LH
人类ALT癌症在ATRX和DAXX中显示出高突变率。尽管众所周知ATRX/DAXX的缺失破坏了H3.3在异染色质处的沉积，但其对H3.3沉积和全局基因组中的翻译后修饰的影响仍不清楚。在这里，我们探讨了磷酸化的H3.3丝氨酸31（H3.3S31ph）在人类ALT癌细胞的动力学。虽然H3.3S31ph仅在大多数人体细胞有丝分裂期间的臂间卫星DNA重复中发现，但在ALT细胞的整个染色体上检测到高水平的H3.3S31ph，这归因于这些细胞中CHK 1活性升高。在这些ALT细胞中，有丝分裂期间CHK 1活性的药物抑制和突变体H3.3S31A的表达导致H3.3S31ph水平的降低，伴随着染色体臂和端粒上磷酸化H2 AX丝氨酸139水平的增加。此外，这些细胞中CHK 1活性的抑制也降低了细胞活力。我们的研究结果表明CHK 1作为H3.3S31激酶的新作用，CHK 1介导的H3.3S31ph在维持ALT癌细胞的染色质完整性和细胞存活中起重要作用。
Human ALT cancers show high mutation rates in ATRX and DAXX. Although it is well known that the absence of ATRX/DAXX disrupts H3.3 deposition at heterochromatin, its impact on H3.3 deposition and post-translational modification in the global genome remains unclear. Here, we explore the dynamics of phosphorylated H3.3 serine 31 (H3.3S31ph) in human ALT cancer cells. While H3.3S31ph is found only at pericentric satellite DNA repeats during mitosis in most somatic human cells, a high level of H3.3S31ph is detected on the entire chromosome in ALT cells, attributable to an elevated CHK1 activity in these cells. Drug inhibition of CHK1 activity during mitosis and expression of mutant H3.3S31A in these ALT cells result in a decrease in H3.3S31ph levels accompanied with increased levels of phosphorylated H2AX serine 139 on chromosome arms and at the telomeres. Furthermore, the inhibition of CHK1 activity in these cells also reduces cell viability. Our findings suggest a novel role of CHK1 as an H3.3S31 kinase, and that CHK1-mediated H3.3S31ph plays an important role in the maintenance of chromatin integrity and cell survival in ALT cancer cells.
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影响因子：
10.5
作者：
Drane, Pascal;Ouararhni, Khalid;Hamiche, Ali
通讯作者：
Hamiche, Ali
影响因子：
16.8
作者：
Iwase, Shigeki;Xiang, Bin;Ghosh, Sharmistha;Ren, Ting;Lewis, Peter W.;Cochrane, Jesse C.;Allis, C. David;Picketts, David J.;Patel, Dinshaw J.;Li, Haitao;Shi, Yang
通讯作者：
Shi, Yang
影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
影响因子：
15.9
作者：
Huh, Michael S.;O'Dea, Tina Price;Picketts, David J.
通讯作者：
Picketts, David J.
影响因子：
4.7
作者：
Conomos D;Pickett HA;Reddel RR
通讯作者：
Reddel RR