Usp16 contributes to somatic stem-cell defects in Down’s syndrome

Maddalena Adorno, Shaheen Sikandar, Siddhartha S. Mitra, Angera Kuo, Benedetta Nicolis di Robilant, Veronica Haro-Acosta, Youcef Ouadah, Marco Quarta, Jacqueline Rodriguez, Dalong Qian, Vadiyala M. Reddy, Samuel Cheshier, Craig C. Garner and Michael F. Clarke ()
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Maddalena Adorno: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Shaheen Sikandar: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Siddhartha S. Mitra: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Angera Kuo: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Benedetta Nicolis di Robilant: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Veronica Haro-Acosta: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Youcef Ouadah: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Marco Quarta: Stanford University School of Medicine
Jacqueline Rodriguez: Stanford University School of Medicine
Dalong Qian: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Vadiyala M. Reddy: Stanford University School of Medicine
Samuel Cheshier: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Craig C. Garner: Stanford University School of Medicine
Michael F. Clarke: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine

Nature, 2013, vol. 501, issue 7467, 380-384

Abstract: Abstract Down’s syndrome results from full or partial trisomy of chromosome 21. However, the consequences of the underlying gene–dosage imbalance on adult tissues remain poorly understood. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from histone H2A on lysine 119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down’s syndrome fibroblasts. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down’s syndrome and could serve as an attractive target to ameliorate some of the associated pathologies.

Date: 2013
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DOI: 10.1038/nature12530

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