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Induction of alternative lengthening of telomeres-associated PML bodies by p53/p21 requires HP1 proteins

¹ Cancer Research Unit and ² Cell Transformation Unit, Children's Medical Research Institute, Westmead 2145, New South Wales, Australia
³ Faculty of Medicine, University of Sydney, New South Wales 2006, Australia

Correspondence to Roger Reddel: rreddel{at}cmri.usyd.edu.au

Alternative lengthening of telomeres (ALT) is a recombination-mediated process that maintains telomeres in telomerase-negative cancer cells. In asynchronously dividing ALT-positive cell populations, a small fraction of the cells have ALT-associated promyelocytic leukemia nuclear bodies (APBs), which contain (TTAGGG)n DNA and telomere-binding proteins. We found that restoring p53 function in ALT cells caused p21 up-regulation, growth arrest/senescence, and a large increase in cells containing APBs. Knockdown of p21 significantly reduced p53-mediated induction of APBs. Moreover, we found that heterochromatin protein 1 (HP1) is present in APBs, and knockdown of HP1 and/or HP1 prevented p53-mediated APB induction, which suggests that HP1-mediated chromatin compaction is required for APB formation. Therefore, although the presence of APBs in a cell line or tumor is an excellent qualitative marker for ALT, the association of APBs with growth arrest/senescence and with "closed" telomeric chromatin, which is likely to repress recombination, suggests there is no simple correlation between ALT activity level and the number of APBs or APB-positive cells.

C.D. Toouli's present address is Bio-Link Australia Pty Ltd, Locomotive Workshop, Eveleigh 2015, New South Wales, Australia.

Abbreviations used in this paper: 4OHT, 4-hydroxytamoxifen; ALT, alternative lengthening of telomeres; APB, ALT-associated PML body; ER, estrogen receptor; HP1, heterochromatin protein 1; LTAg, SV40 large T antigen; PCNA, proliferating cell nuclear antigen; PML, promyelocytic leukemia; SA, senescence associated; wt, wild type.

© 2009 Jiang et al.
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