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Molecular and Cellular Biology, May 2006, p. 3659-3671, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3659-3671.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Retinoblastoma Protein Regulates Pericentric Heterochromatin

Christian E. Isaac,1,3 Sarah M. Francis,1,3 Alison L. Martens,1 Lisa M. Julian,1,3 Laurie A. Seifried,1,3 Natalie Erdmann,4 Ulrich K. Binné,5 Lea Harrington,4 Piotr Sicinski,6 Nathalie G. Bérubé,2,3 Nicholas J. Dyson,5 and Frederick A. Dick1,2,3,5*

London Regional Cancer Program,1 Children's Health Research Institute,2 Department of Biochemistry, University of Western Ontario, London, Ontario, Canada,3 Campbell Family Institute for Breast Cancer Research, Toronto, Ontario, Canada,4 Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts,5 Dana-Farber Cancer Institute, Boston, Massachusetts6

Received 7 October 2005/ Returned for modification 9 November 2005/ Accepted 3 February 2006

The retinoblastoma protein (pRb) has been proposed to regulate cell cycle progression in part through its ability to interact with enzymes that modify histone tails and create a repressed chromatin structure. We created a mutation in the murine Rb1 gene that disrupted pRb's ability to interact with these enzymes to determine if it affected cell cycle control. Here, we show that loss of this interaction slows progression through mitosis and causes aneuploidy. Our experiments reveal that while the LXCXE binding site mutation does not disrupt pRb's interaction with the Suv4-20h histone methyltransferases, it dramatically reduces H4-K20 trimethylation in pericentric heterochromatin. Disruption of heterochromatin structure in this chromosomal region leads to centromere fusions, chromosome missegregation, and genomic instability. These results demonstrate the surprising finding that pRb uses the LXCXE binding cleft to control chromatin structure for the regulation of events beyond the G1-to-S-phase transition.

* Corresponding author. Mailing address: Cancer Research Labs, 790 Commissioners Road East, London, Ontario, Canada, N6A 4L6. Phone: (519) 685-8620. Fax: (519) 685-8620. E-mail: fdick{at}uwo.ca.

Molecular and Cellular Biology, May 2006, p. 3659-3671, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3659-3671.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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