Endogenous DNA Damage Leads to p53-Independent Deficits in Replicative Fitness in Fetal Murine Fancd2−/− Hematopoietic Stem and Progenitor Cells

Young me Yoon, Kelsie J. Storm, Ashley N. Kamimae-Lanning, Natalya A. Goloviznina, Peter Kurre

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Our mechanistic understanding of Fanconi anemia (FA) pathway function in hematopoietic stem and progenitor cells (HSPCs) owes much to their role in experimentally induced DNA crosslink lesion repair. In bone marrow HSPCs, unresolved stress confers p53-dependent apoptosis and progressive cell attrition. The role of FA proteins during hematopoietic development, in the face of physiological replicative demand, remains elusive. Here, we reveal a fetal HSPC pool in Fancd2−/− mice with compromised clonogenicity and repopulation. Without experimental manipulation, fetal Fancd2−/− HSPCs spontaneously accumulate DNA strand breaks and RAD51 foci, associated with a broad transcriptional DNA-damage response, and constitutive activation of ATM as well as p38 stress kinase. Remarkably, the unresolved stress during rapid HSPC pool expansion does not trigger p53 activation and apoptosis; rather, it constrains proliferation. Collectively our studies point to a role for the FA pathway during hematopoietic development and provide a new model for studying the physiological function of FA proteins.

Original languageEnglish (US)
Pages (from-to)840-853
Number of pages14
JournalStem Cell Reports
Volume7
Issue number5
DOIs
StatePublished - Nov 8 2016

Fingerprint

Fanconi Anemia Complementation Group Proteins
Hematopoietic Stem Cells
DNA Damage
DNA
Chemical activation
Apoptosis
Automatic teller machines
Bone
Repair
Phosphotransferases
Fanconi Anemia
Fetal Stem Cells
DNA Breaks
Bone Marrow

Keywords

  • bone marrow failure
  • development
  • Fanconi anemia
  • hematopoiesis
  • stem cells

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Endogenous DNA Damage Leads to p53-Independent Deficits in Replicative Fitness in Fetal Murine Fancd2−/− Hematopoietic Stem and Progenitor Cells. / Yoon, Young me; Storm, Kelsie J.; Kamimae-Lanning, Ashley N.; Goloviznina, Natalya A.; Kurre, Peter.

In: Stem Cell Reports, Vol. 7, No. 5, 08.11.2016, p. 840-853.

Research output: Contribution to journalArticle

Yoon, Young me ; Storm, Kelsie J. ; Kamimae-Lanning, Ashley N. ; Goloviznina, Natalya A. ; Kurre, Peter. / Endogenous DNA Damage Leads to p53-Independent Deficits in Replicative Fitness in Fetal Murine Fancd2−/− Hematopoietic Stem and Progenitor Cells. In: Stem Cell Reports. 2016 ; Vol. 7, No. 5. pp. 840-853.
@article{cc5075ec03ed4b2ea361c227a0514a94,
title = "Endogenous DNA Damage Leads to p53-Independent Deficits in Replicative Fitness in Fetal Murine Fancd2−/− Hematopoietic Stem and Progenitor Cells",
abstract = "Our mechanistic understanding of Fanconi anemia (FA) pathway function in hematopoietic stem and progenitor cells (HSPCs) owes much to their role in experimentally induced DNA crosslink lesion repair. In bone marrow HSPCs, unresolved stress confers p53-dependent apoptosis and progressive cell attrition. The role of FA proteins during hematopoietic development, in the face of physiological replicative demand, remains elusive. Here, we reveal a fetal HSPC pool in Fancd2−/− mice with compromised clonogenicity and repopulation. Without experimental manipulation, fetal Fancd2−/− HSPCs spontaneously accumulate DNA strand breaks and RAD51 foci, associated with a broad transcriptional DNA-damage response, and constitutive activation of ATM as well as p38 stress kinase. Remarkably, the unresolved stress during rapid HSPC pool expansion does not trigger p53 activation and apoptosis; rather, it constrains proliferation. Collectively our studies point to a role for the FA pathway during hematopoietic development and provide a new model for studying the physiological function of FA proteins.",
keywords = "bone marrow failure, development, Fanconi anemia, hematopoiesis, stem cells",
author = "Yoon, {Young me} and Storm, {Kelsie J.} and Kamimae-Lanning, {Ashley N.} and Goloviznina, {Natalya A.} and Peter Kurre",
year = "2016",
month = "11",
day = "8",
doi = "10.1016/j.stemcr.2016.09.005",
language = "English (US)",
volume = "7",
pages = "840--853",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - Endogenous DNA Damage Leads to p53-Independent Deficits in Replicative Fitness in Fetal Murine Fancd2−/− Hematopoietic Stem and Progenitor Cells

AU - Yoon, Young me

AU - Storm, Kelsie J.

AU - Kamimae-Lanning, Ashley N.

AU - Goloviznina, Natalya A.

AU - Kurre, Peter

PY - 2016/11/8

Y1 - 2016/11/8

N2 - Our mechanistic understanding of Fanconi anemia (FA) pathway function in hematopoietic stem and progenitor cells (HSPCs) owes much to their role in experimentally induced DNA crosslink lesion repair. In bone marrow HSPCs, unresolved stress confers p53-dependent apoptosis and progressive cell attrition. The role of FA proteins during hematopoietic development, in the face of physiological replicative demand, remains elusive. Here, we reveal a fetal HSPC pool in Fancd2−/− mice with compromised clonogenicity and repopulation. Without experimental manipulation, fetal Fancd2−/− HSPCs spontaneously accumulate DNA strand breaks and RAD51 foci, associated with a broad transcriptional DNA-damage response, and constitutive activation of ATM as well as p38 stress kinase. Remarkably, the unresolved stress during rapid HSPC pool expansion does not trigger p53 activation and apoptosis; rather, it constrains proliferation. Collectively our studies point to a role for the FA pathway during hematopoietic development and provide a new model for studying the physiological function of FA proteins.

AB - Our mechanistic understanding of Fanconi anemia (FA) pathway function in hematopoietic stem and progenitor cells (HSPCs) owes much to their role in experimentally induced DNA crosslink lesion repair. In bone marrow HSPCs, unresolved stress confers p53-dependent apoptosis and progressive cell attrition. The role of FA proteins during hematopoietic development, in the face of physiological replicative demand, remains elusive. Here, we reveal a fetal HSPC pool in Fancd2−/− mice with compromised clonogenicity and repopulation. Without experimental manipulation, fetal Fancd2−/− HSPCs spontaneously accumulate DNA strand breaks and RAD51 foci, associated with a broad transcriptional DNA-damage response, and constitutive activation of ATM as well as p38 stress kinase. Remarkably, the unresolved stress during rapid HSPC pool expansion does not trigger p53 activation and apoptosis; rather, it constrains proliferation. Collectively our studies point to a role for the FA pathway during hematopoietic development and provide a new model for studying the physiological function of FA proteins.

KW - bone marrow failure

KW - development

KW - Fanconi anemia

KW - hematopoiesis

KW - stem cells

UR - http://www.scopus.com/inward/record.url?scp=84992088546&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84992088546&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2016.09.005

DO - 10.1016/j.stemcr.2016.09.005

M3 - Article

C2 - 27720904

AN - SCOPUS:84992088546

VL - 7

SP - 840

EP - 853

JO - Stem Cell Reports

JF - Stem Cell Reports

SN - 2213-6711

IS - 5

ER -