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Apoptotic histone modification inhibits nuclear transport by regulating RCC1

Nature Cell Biology volume 11, pages 36–45 (2009)Cite this article

An Erratum to this article was published on 01 February 2009

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Abstract

A number of signalling pathways have been identified that regulate apoptosis, but the mechanism that initiates apoptosis remains incompletely understood. We have found that the nuclear RanGTP level is diminished during the early stages of apoptosis, which correlates with immobilization of RCC1 on the chromosomes. Furthermore, the expression of phosphomimetic histone H2B or caspase-activated Mst1 immobilizes RCC1 and causes reduction of nuclear RanGTP levels, which leads to inactivation of the nuclear transport machinery. As a consequence, nuclear localization signal (NLS)-containing proteins, including NF-κB–p65, remain bound to importins α and β in the cytoplasm. Knocking down Mst1 allows resumption of nuclear transport and the nuclear entry of NF-κB–p65, which have important roles in rescuing cells from apoptosis. Therefore, we propose that RCC1 reads the histone code created by caspase-activated Mst1 to initiate apoptosis by reducing the level of RanGTP in the nucleus.

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Figure 1: The RanGTP gradient collapses during early stages of apoptosis, whereas the nuclear envelope remains intact.
Figure 2: Immobilization of RCC1 on the chromatin during early stages of apoptosis.
Figure 3: H2BS14 phosphomimetic causes the immobilization of RCC1 on the chromosome and reduction of nuclear RanGTP levels.
Figure 4: RCC1 is trapped on the histone H2B S14 phosphorylated nucleosome with Ran.
Figure 5: Active Mst1 causes the immobilization of RCC1 on the chromosome and the reduction of nuclear RanGTP level.
Figure 6: NLS containing protein remains bound to importins α and β in the cytoplasm as a result of the collapse of RanGTP gradient.
Figure 7: Mst1 RNAi restored nuclear entry of NF-κB and prevented cell death induced by VP16.
Figure 8: Phosphorylation of H2BS14 leads to impairment of nuclear transport.

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Change history

  • 16 December 2008

    In the version of this article initially published online, the bands showing NF-κB-p50 in Figure 1b, and the columns for GFP and mCherry in Figure 5a were incorrectly labelled. The figure 7b legend should also read “...(15, 5, 2 μl)” instead of “...(10, 5, 2 μl).

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Acknowledgements

This work was supported by Academic Research Fund, Ministry of Education, Singapore (ARC 7/06) and Biomedical Research Council, A*STAR, Singapore (05/1/22/19/388).

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Authors and Affiliations

  1. Division of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, 637551, Singapore

    Chi-Hang Wong, Hei Chan, Chin-Yee Ho, Soak-Kuan Lai, Kheng-Sze Chan, Cheng-Gee Koh & Hoi-Yeung Li

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Contributions

C.H.W. carried out most of the experiments; H.C., C.Y.H., S.K.L. and K.S.C. assisted with some experiments; H.Y.L., C.H.W. and C.G.K. conceived and designed the project; H.Y.L, C.G.K., H.C. and C.H.W. wrote the manuscript. All authors participated in data analysis. All authors read and edited the manuscript.

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Correspondence to Cheng-Gee Koh or Hoi-Yeung Li.

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The authors declare no competing financial interests.

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Wong, CH., Chan, H., Ho, CY. et al. Apoptotic histone modification inhibits nuclear transport by regulating RCC1. Nat Cell Biol 11, 36–45 (2009). https://doi.org/10.1038/ncb1810

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