title: Tpp1/Acd maintains genomic stability through a complex role in telomere protection.
abstract: Telomeres serve to protect the ends of chromosomes, and failure to maintain telomeres can lead to dramatic genomic instability. Human TPP1 was identified as a protein which interacts with components of a telomere cap complex, but does not directly bind to telomeric DNA. While biochemical interactions indicate a function in telomere biology, much remains to be learned regarding the roles of TPP1 in vivo. We previously reported the positional cloning of the gene responsible for the adrenocortical dysplasia (acd) mouse phenotype, which revealed a mutation in the mouse homologue encoding TPP1. We find that cells from homozygous acd mice harbor chromosomes fused at telomere sequences, demonstrating a role in telomere protection in vivo. Surprisingly, our studies also reveal fusions and radial structures lacking internal telomere sequences, which are not anticipated from a simple deficiency in telomere protection. Employing spectral karyotyping and telomere FISH in a combined approach, we have uncovered a striking pattern; fusions with telomeric sequences involve nonhomologous chromosomes while those lacking telomeric sequences involve homologues. Together, these studies show that Tpp1/Acd plays a vital role in telomere protection, but likely has additional functions yet to be defined.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Metabolism, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Else
authors.forename: Brian K
authors.initials: BK
authors.lastname: Theisen
authors.forename: Yipin
authors.initials: Y
authors.lastname: Wu
authors.forename: Janna E
authors.initials: JE
authors.lastname: Hutz
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Keegan
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hammer
authors.forename: David O
authors.initials: DO
authors.lastname: Ferguson
mesh_terms: D000303:Adrenal Cortex Diseases / Q000235:genetics* / Q000473:pathology; D000705:Anaphase; D000818:Animals; D002478:Cells, Cultured; D002875:Chromosomes / Q000235:genetics; D005347:Fibroblasts; D042822:Genomic Instability; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000089804:Shelterin Complex; D032681:Spectral Karyotyping; D016615:Telomere / Q000502:physiology*; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C495876:ACD protein, human; C544060:Acd protein, mouse; D012333:RNA, Messenger; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins