title: Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction.
abstract: The tumour suppressor p53 activates Puma-dependent apoptosis and p21-dependent cell-cycle arrest in response to DNA damage. Deletion of p21 improved stem-cell function and organ maintenance in progeroid mice with dysfunctional telomeres, but the function of Puma has not been investigated in this context. Here we show that deletion of Puma improves stem- and progenitor-cell function, organ maintenance and lifespan of telomere-dysfunctional mice. Puma deletion impairs the clearance of stem and progenitor cells that have accumulated DNA damage as a consequence of critically short telomeres. However, further accumulation of DNA damage in these rescued progenitor cells leads to increasing activation of p21. RNA interference experiments show that upregulation of p21 limits proliferation and evolution of chromosomal imbalances of Puma-deficient stem and progenitor cells with dysfunctional telomeres. These results provide experimental evidence that p53-dependent apoptosis and cell-cycle arrest act in cooperating checkpoints limiting tissue maintenance and evolution of chromosomal instability at stem- and progenitor-cell levels in response to telomere dysfunction. Selective inhibition of Puma-dependent apoptosis can result in temporary improvements in maintenance of telomere-dysfunctional organs.
authors.affiliation: Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, 89081 Ulm, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Sperka
authors.forename: Zhangfa
authors.initials: Z
authors.lastname: Song
authors.forename: Yohei
authors.initials: Y
authors.lastname: Morita
authors.forename: Kodandaramireddy
authors.initials: K
authors.lastname: Nalapareddy
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Guachalla
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Begus-Nahrmann
authors.forename: Martin D
authors.initials: MD
authors.lastname: Burkhalter
authors.forename: Monika
authors.initials: M
authors.lastname: Mach
authors.forename: Falk
authors.initials: F
authors.lastname: Schlaudraff
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D048708:Cell Growth Processes / Q000235:genetics; D043171:Chromosomal Instability; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins