Pluripotential Hematopoietic Stem-Cells in Adult-Mouse Brain

Bartlett, PF (1982) Pluripotential Hematopoietic Stem-Cells in Adult-Mouse Brain. Proceedings of the National Academy of Sciences of the United States of America-Biological Sciences, 79 8: 2722-2725. doi:10.1073/pnas.79.8.2722


Author Bartlett, PF
Title Pluripotential Hematopoietic Stem-Cells in Adult-Mouse Brain
Journal name Proceedings of the National Academy of Sciences of the United States of America-Biological Sciences   Check publisher's open access policy
ISSN 0027-8424
Publication date 1982-01-01
Year available 1982
Sub-type Article (original research)
DOI 10.1073/pnas.79.8.2722
Open Access Status Not Open Access
Volume 79
Issue 8
Start page 2722
End page 2725
Total pages 4
Publisher NATL ACAD SCIENCES
Language eng
Abstract Hematopoietic stem and progenitor cells (HSPCs) are vulnerable to endogenous damage and defects in DNA repair can limit their function. The 2 single-stranded DNA (ssDNA) binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response; however, their overlapping roles during normal physiology are incompletely understood. We generated mice in which both Ssb1 and Ssb2 were constitutively or conditionally deleted. Constitutive Ssb1/Ssb2 double knockout (DKO) caused early embryonic lethality, whereas conditional Ssb1/Ssb2 double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featuring stem and progenitor cell depletion, a phenotype unexpected from the previously reported single knockout models of Ssb1 or Ssb2 Mechanistically, cDKO HSPCs showed altered replication fork dynamics, massive accumulation of DNA damage, genome-wide double-strand breaks enriched at Ssb-binding regions and CpG islands, together with the accumulation of R-loops and cytosolic ssDNA. Transcriptional profiling of cDKO HSPCs revealed the activation of p53 and interferon (IFN) pathways, which enforced cell cycling in quiescent HSPCs, resulting in their apoptotic death. The rapid cell death phenotype was reproducible in in vitro cultured cDKO-hematopoietic stem cells, which were significantly rescued by nucleotide supplementation or after depletion of p53. Collectively, Ssb1 and Ssb2 control crucial aspects of HSPC function, including proliferation and survival in vivo by resolving replicative stress to maintain genomic stability.
Keyword Biology
Life Sciences & Biomedicine - Other Topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 CA129537
R01 CA154320
R01 GM109768
R01 GM112131
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: ResearcherID Downloads - Archived
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 97 times in Thomson Reuters Web of Science Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 11 Jul 2012, 02:06:35 EST by System User on behalf of Scholarly Communication and Digitisation Service