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Molecular and Cellular Biology, February 2007, p. 949-962, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01639-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

HP1 Proteins Are Essential for a Dynamic Nuclear Response That Rescues the Function of Perturbed Heterochromatin in Primary Human Cells ^,

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,¹ University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania 19104²

Received 1 September 2006/ Returned for modification 19 October 2006/ Accepted 30 October 2006

Cellular information is encoded genetically in the DNA nucleotide sequence and epigenetically by the "histone code," DNA methylation, and higher-order packaging of DNA into chromatin. Cells possess intricate mechanisms to sense and repair damage to DNA and the genetic code. However, nothing is known of the mechanisms, if any, that repair and/or compensate for damage to epigenetically encoded information, predicted to result from perturbation of DNA and histone modifications or other changes in chromatin structure. Here we show that primary human cells respond to a variety of small molecules that perturb DNA and histone modifications by recruiting HP1 proteins to sites of altered pericentromeric heterochromatin. This response is essential to maintain the HP1-binding kinetochore protein hMis12 at kinetochores and to suppress catastrophic mitotic defects. Recruitment of HP1 proteins to pericentromeres depends on histone H3.3 variant deposition, mediated by the HIRA histone chaperone. These data indicate that defects in pericentromeric epigenetic heterochromatin modifications initiate a dynamic HP1-dependent response that rescues pericentromeric heterochromatin function and is essential for viable progression through mitosis.

Published ahead of print on 13 November 2006.

Supplemental material for this article may be found at http://mcb.asm.org/.

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