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Molecular and Cellular Biology, February 2009, p. 758-770, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.01047-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human UBN1 Is an Ortholog of Yeast Hpc2p and Has an Essential Role in the HIRA/ASF1a Chromatin-Remodeling Pathway in Senescent Cells{triangledown}

Gowrishankar Banumathy,1 Neeta Somaiah,1 Rugang Zhang,1 Yong Tang,2 Jason Hoffmann,2 Mark Andrake,1 Hugo Ceulemans,3 David Schultz,2 Ronen Marmorstein,2 and Peter D. Adams1*

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,1 Wistar Institute, Philadelphia, Pennsylvania 19104,2 Katholieke Universiteit Leuven, Leuven, Belgium3

Received 3 July 2008/ Returned for modification 28 July 2008/ Accepted 9 November 2008

Cellular senescence is an irreversible proliferation arrest, tumor suppression process and likely contributor to tissue aging. Senescence is often characterized by domains of facultative heterochromatin, called senescence-associated heterochromatin foci (SAHF), which repress expression of proliferation-promoting genes. Given its likely contribution to tumor suppression and tissue aging, it is essential to identify all components of the SAHF assembly pathway. Formation of SAHF in human cells is driven by a complex of histone chaperones, namely, HIRA and ASF1a. In yeast, the complex orthologous to HIRA/ASF1a contains two additional proteins, Hpc2p and Hir3p. Using a sophisticated approach to search for remote orthologs conserved in multiple species through evolution, we identified the HIRA-associated proteins, UBN1 and UBN2, as candidate human orthologs of Hpc2p. We show that the Hpc2-related domain of UBN1, UBN2, and Hpc2p is an evolutionarily conserved HIRA/Hir-binding domain, which directly interacts with the N-terminal WD repeats of HIRA/Hir. UBN1 binds to proliferation-promoting genes that are repressed by SAHF and associates with histone methyltransferase activity that methylates lysine 9 of histone H3, a site that is methylated in SAHF. UBN1 is indispensable for formation of SAHF. We conclude that UBN1 is an ortholog of yeast Hpc2p and a novel regulator of senescence.

* Corresponding author. Present address: University of Glasgow, Cancer Research UK Beatson Labs, Garscube Estate, Switchback Road, Glasgow G61 1BD, United Kingdom. Phone: (0) 141 330 2306. Fax: (0) 141 942 6521. E-mail: p.adams{at}beatson.gla.ac.uk

{triangledown} Published ahead of print on 24 November 2008.

Molecular and Cellular Biology, February 2009, p. 758-770, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.01047-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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