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Lack of Bcl11b tumor suppressor results in vulnerability to DNA replication stress and damages

Oncogene volume 26, pages 5840–5850 (2007)Cite this article

Abstract

Bcl11b/Rit1 is involved in T-cell development and undergoes chromosomal rearrangements in human T-cell leukemias. Thymocytes of Bcl11b−/− newborn mice exhibit apoptosis at a certain developmental stage when thymocytes re-enter into the cell-cycle. Here, we show that Bcl11b-knockdown T-cell lines, when exposed to growth stimuli, exhibited apoptosis at the S phase with concomitant decreases in a cell-cycle inhibitor, p27 and an antiapoptotic protein, Bcl-xL, owing to transcriptional repression. This repression was a likely consequence of the impairment of Sirt1, a nicotinamide adenine dinucleotide-dependent deacetylase associating with Bcl11b. Activation of the apoptotic process cleaved the mediator protein, Claspin, and inhibited phosphorylation of cell-cycle checkpoint kinase 1 (Chk1) that plays a central role in sensing and responding to incomplete replication. Bcl11b−/− thymocytes also failed to phosphorylate Chk1 when UV irradiated. These results implicate Bcl11b in the remedy for DNA replication stress and maintenance of genomic integrity.

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Acknowledgements

We thank O Niwa and A Balmain for helpful comments on the paper. This work was supported by grants-in-aid for Cancer Research from the Ministries of Education, Science, Art and Sports, and of Health and Welfare of Japan.

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Authors and Affiliations

  1. Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    K Kamimura, Y Mishima, M Obata, T Endo, Y Aoyagi & R Kominami

  2. Center for Transdisciplinary Research, Niigata University, Niigata, Japan

    Y Mishima, M Obata & R Kominami

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  1. K Kamimura
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Correspondence to R Kominami.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Kamimura, K., Mishima, Y., Obata, M. et al. Lack of Bcl11b tumor suppressor results in vulnerability to DNA replication stress and damages. Oncogene 26, 5840–5850 (2007). https://doi.org/10.1038/sj.onc.1210388

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  • DOI: https://doi.org/10.1038/sj.onc.1210388

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