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PML induces compaction, TRF2 depletion and DNA damage signaling at telomeres and promotes their alternative lengthening.
J Cell Sci 2015; 128(10):1887-900JC

Abstract

The alternative lengthening of telomeres (ALT) mechanism allows cancer cells to escape senescence and apoptosis in the absence of active telomerase. A characteristic feature of this pathway is the assembly of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) at telomeres. Here, we dissected the role of APBs in a human ALT cell line by performing an RNA interference screen using an automated 3D fluorescence microscopy platform and advanced 3D image analysis. We identified 29 proteins that affected APB formation, which included proteins involved in telomere and chromatin organization, protein sumoylation and DNA repair. By integrating and extending these findings, we found that APB formation induced clustering of telomere repeats, telomere compaction and concomitant depletion of the shelterin protein TRF2 (also known as TERF2). These APB-dependent changes correlated with the induction of a DNA damage response at telomeres in APBs as evident by a strong enrichment of the phosphorylated form of the ataxia telangiectasia mutated (ATM) kinase. Accordingly, we propose that APBs promote telomere maintenance by inducing a DNA damage response in ALT-positive tumor cells through changing the telomeric chromatin state to trigger ATM phosphorylation.

Authors+Show Affiliations

Research Group Genome Organization & Function, Deutsches Krebsforschungszentrum (DKFZ) & BioQuant, 69120 Heidelberg, Germany.Research Group Genome Organization & Function, Deutsches Krebsforschungszentrum (DKFZ) & BioQuant, 69120 Heidelberg, Germany.Research Group Genome Organization & Function, Deutsches Krebsforschungszentrum (DKFZ) & BioQuant, 69120 Heidelberg, Germany.Research Group Genome Organization & Function, Deutsches Krebsforschungszentrum (DKFZ) & BioQuant, 69120 Heidelberg, Germany.Department of Bioinformatics and Functional Genomics, Biomedical Computer Vision Group, University of Heidelberg & DKFZ, BioQuant, IPMB, 69120 Heidelberg, Germany.Department of Bioinformatics and Functional Genomics, Biomedical Computer Vision Group, University of Heidelberg & DKFZ, BioQuant, IPMB, 69120 Heidelberg, Germany.ViroQuant-CellNetworks RNAi Screening Facility, University of Heidelberg & BioQuant, 69120 Heidelberg, Germany.Research Group Genome Organization & Function, Deutsches Krebsforschungszentrum (DKFZ) & BioQuant, 69120 Heidelberg, Germany Karsten.Rippe@dkfz.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25908860

Citation

Osterwald, Sarah, et al. "PML Induces Compaction, TRF2 Depletion and DNA Damage Signaling at Telomeres and Promotes Their Alternative Lengthening." Journal of Cell Science, vol. 128, no. 10, 2015, pp. 1887-900.
Osterwald S, Deeg KI, Chung I, et al. PML induces compaction, TRF2 depletion and DNA damage signaling at telomeres and promotes their alternative lengthening. J Cell Sci. 2015;128(10):1887-900.
Osterwald, S., Deeg, K. I., Chung, I., Parisotto, D., Wörz, S., Rohr, K., ... Rippe, K. (2015). PML induces compaction, TRF2 depletion and DNA damage signaling at telomeres and promotes their alternative lengthening. Journal of Cell Science, 128(10), pp. 1887-900. doi:10.1242/jcs.148296.
Osterwald S, et al. PML Induces Compaction, TRF2 Depletion and DNA Damage Signaling at Telomeres and Promotes Their Alternative Lengthening. J Cell Sci. 2015 May 15;128(10):1887-900. PubMed PMID: 25908860.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PML induces compaction, TRF2 depletion and DNA damage signaling at telomeres and promotes their alternative lengthening. AU - Osterwald,Sarah, AU - Deeg,Katharina I, AU - Chung,Inn, AU - Parisotto,Daniel, AU - Wörz,Stefan, AU - Rohr,Karl, AU - Erfle,Holger, AU - Rippe,Karsten, Y1 - 2015/04/23/ PY - 2014/08/27/received PY - 2015/03/23/accepted PY - 2015/4/25/entrez PY - 2015/4/25/pubmed PY - 2016/4/6/medline KW - ALT KW - ALT-associated PML nuclear body KW - APB KW - Alternative lengthening of telomeres KW - DNA repair KW - PML nuclear bodies SP - 1887 EP - 900 JF - Journal of cell science JO - J. Cell. Sci. VL - 128 IS - 10 N2 - The alternative lengthening of telomeres (ALT) mechanism allows cancer cells to escape senescence and apoptosis in the absence of active telomerase. A characteristic feature of this pathway is the assembly of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) at telomeres. Here, we dissected the role of APBs in a human ALT cell line by performing an RNA interference screen using an automated 3D fluorescence microscopy platform and advanced 3D image analysis. We identified 29 proteins that affected APB formation, which included proteins involved in telomere and chromatin organization, protein sumoylation and DNA repair. By integrating and extending these findings, we found that APB formation induced clustering of telomere repeats, telomere compaction and concomitant depletion of the shelterin protein TRF2 (also known as TERF2). These APB-dependent changes correlated with the induction of a DNA damage response at telomeres in APBs as evident by a strong enrichment of the phosphorylated form of the ataxia telangiectasia mutated (ATM) kinase. Accordingly, we propose that APBs promote telomere maintenance by inducing a DNA damage response in ALT-positive tumor cells through changing the telomeric chromatin state to trigger ATM phosphorylation. SN - 1477-9137 UR - https://www.unboundmedicine.com/medline/citation/25908860/PML_induces_compaction_TRF2_depletion_and_DNA_damage_signaling_at_telomeres_and_promotes_their_alternative_lengthening_ L2 - http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=25908860 DB - PRIME DP - Unbound Medicine ER -