HP1-mediated formation of alternative lengthening of telomeres-associated PML bodies requires HIRA but not ASF1a.

Abstract

Approximately 10% of cancers use recombination-mediated Alternative Lengthening of Telomeres (ALT) instead of telomerase to prevent telomere shortening. A characteristic of cells that utilize ALT is the presence of ALT-associated PML nuclear bodies (APBs) containing (TTAGGG)n DNA, telomere binding proteins, DNA recombination proteins, and heterochromatin protein 1 (HP1). The function of APBs is unknown and it is possible that they are functionally heterogeneous. Most ALT cells lack functional p53, and restoration of the p53/p21 pathway in these cells results in growth arrest/senescence and a substantial increase in the number of large APBs that is dependent on two HP1 isoforms, HP1α and HP1γ. Here we investigated the mechanism of HP1-mediated APB formation, and found that histone chaperones, HIRA and ASF1a, are present in APBs following activation of the p53/p21 pathway in ALT cells. HIRA and ASF1a were also found to colocalize inside PML bodies in normal fibroblasts approaching senescence, providing evidence for the existence of a senescence-associated ASF1a/HIRA complex inside PML bodies, consistent with a role for these proteins in induction of senescence in both normal and ALT cells. Moreover, knockdown of HIRA but not ASF1a significantly reduced p53-mediated induction of large APBs, with a concomitant reduction of large HP1 foci. We conclude that HIRA, in addition to its physical and functional association with ASF1a, plays a unique, ASF1a-independent role, which is required for the localization of HP1 to PML bodies and thus for APB formation.

• Authors: Wei-Qin Jiang, Akira Nguyen, Ying Cao, Andy C-M Chang, Roger R Reddel
• Journal: PloS one (PLoS One) Vol. 6 Issue 2 Pg. e17036 (Feb 15 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21347226 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ASF1A protein, human
• CBX5 protein, human
• Cell Cycle Proteins
• Chromosomal Proteins, Non-Histone
• Cyclin-Dependent Kinase Inhibitor p21
• HIRA protein, human
• Histone Chaperones
• Molecular Chaperones
• Transcription Factors
• Tumor Suppressor Protein p53
• Chromobox Protein Homolog 5

Topics

• Active Transport, Cell Nucleus
• Animals
• Cell Cycle Proteins (deficiency, genetics, metabolism)
• Cell Nucleolus (metabolism)
• Cell Nucleus (metabolism)
• Cellular Senescence
• Chromobox Protein Homolog 5
• Chromosomal Proteins, Non-Histone (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Gene Knockdown Techniques
• HeLa Cells
• Histone Chaperones (deficiency, genetics, metabolism)
• Humans
• Molecular Chaperones
• Telomere Homeostasis
• Transcription Factors (deficiency, genetics, metabolism)
• Tumor Suppressor Protein p53 (metabolism)