Induction of alternative lengthening of telomeres-associated PML bodies by p53/p21 requires HP1 proteins.
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 HP1alpha and/or HP1gamma 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.
Jiang
Wei-Qin
WQ
Cancer Research Unit, Children's Medical Research Institute, Westmead 2145, New South Wales, Australia.
Zhong
Ze-Huai
ZH
Nguyen
Akira
A
Henson
Jeremy D
JD
Toouli
Christian D
CD
Braithwaite
Antony W
AW
Reddel
Roger R
RR
D048868:Adaptor Proteins, Signal Transducing; D000957:Antigens, Viral, Tumor / Q000378:metabolism; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2 / Q000032:analysis / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism; D034622:RNA Interference; D016615:Telomere / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000032:analysis; D035341:Telomeric Repeat Binding Protein 2 / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D000957:Antigens, Viral, Tumor; C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; C465618:PCNP protein, human; C504753:TERF2 protein, human; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; D000090266:Chromobox Protein Homolog 5; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2