title: Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation.
abstract: The shelterin complex plays dual functions in telomere homeostasis by recruiting telomerase and preventing the activation of a DNA damage response at telomeric ends. Somatic stem cells require telomerase activity, as evidenced by progressive stem cell loss leading to bone marrow failure in hereditary dyskeratosis congenita. Recent work demonstrates that dyskeratosis congenita can also arise from mutations in specific shelterin genes, although little is known about shelterin functions in somatic stem cells. We found that mouse hematopoietic stem cells (HSCs) are acutely sensitive to inactivation of the shelterin gene Acd, encoding TPP1. Homozygosity for a hypomorphic acd allele preserved the emergence and expansion of fetal HSCs but led to profoundly defective function in transplantation assays. Upon complete Acd inactivation, HSCs expressed p53 target genes, underwent cell cycle arrest, and were severely depleted within days, leading to hematopoietic failure. TPP1 loss induced increased telomeric fusion events in bone marrow progenitors. However, unlike in epidermal stem cells, p53 deficiency did not rescue TPP1-deficient HSCs, indicating that shelterin dysfunction has unique effects in different stem cell populations. Because the consequences of telomere shortening are progressive and unsynchronized, acute loss of shelterin function represents an attractive alternative for studying telomere crisis in hematopoietic progenitors.
authors: Morgan
authors: M
authors: Jones
authors: Gail
authors: G
authors: Osawa
authors: Joshua A
authors: JA
authors: Regal
authors: Daniel N
authors: DN
authors: Weinberg
authors: James
authors: J
authors: Taggart
authors: Hande
authors: H
authors: Kocak
authors: Ann
authors: A
authors: Friedman
authors: David O
authors: DO
authors: Ferguson
authors: Catherine E
authors: CE
authors: Keegan
authors: Ivan
authors: I
authors: Maillard
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002478:Cells, Cultured; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D004789:Enzyme Activation; D059565:G2 Phase Cell Cycle Checkpoints; D005804:Genes, Lethal; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010198:Pancytopenia / Q000235:genetics; D059506:Telomere Shortening; D034501:Telomere-Binding Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: C544060:Acd protein, mouse; D034501:Telomere-Binding Proteins; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7