DNA repair is limiting for haematopoietic stem cells during ageing

Nijnik, Anastasia; Woodbine, Lisa; Marchetti, Caterina; Dawson, Sara J.; Lambe, Teresa; Liu, Cong; Rodrigues, Neil P.; Crockford, Tanya L.; Cabuy, Erik; Vindigni, Alessandro; Enver, Tariq; Bell, John I.; Slijepčević, Predrag; Goodnow, Christopher C.; Jeggo, Penelope A.; Cornall, Richard J.

doi:10.1038/nature05875

Cited by 470 publications

(383 citation statements)

References 42 publications

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“…The phenotypic and functional alterations we highlighted in the KSL compartment of irradiated mice several weeks after exposure resemble observations reported in studies performed with aged mice and transgenic mice with DNA damage repair deficiencies [31][32][33]. To reveal possible additional similarities, we assessed stem/progenitor cells from 3-and 6-Gy irradiated mice for P-selectin cell-surface expression, genomic damage accumulation measured by c-H2AX foci, and frequency of apoptotic events.…”

Section: The Stem/progenitor Compartment Of Irradiated Mice Resemblessupporting

confidence: 64%

Phenotypic and Functional Changes Induced in Hematopoietic Stem/Progenitor Cells After Gamma-Ray Radiation Exposure

et al. 2009

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Ionizing radiation (IR) exposure causes rapid and acute bone marrow (BM) suppression that is reversible for nonlethal doses. Evidence is accumulating that IR can also provoke long-lasting residual hematopoietic injury. To better understand these effects, we analyzed phenotypic and functional changes in the stem/progenitor compartment of irradiated mice over a 10-week period. We found that hematopoietic stem cells (HSCs) identified by their repopulating ability continued to segregate within the Hoechst dye excluding ''side population (SP)'' early after IR exposure. However, transient phenotypic changes were observed within this cell population: Sca-1 (S) and c-Kit (K) expression levels were increased and severely reduced, respectively, with a concurrent increase in the proportion of SP SK cells positive for established indicators of the presence of HSCs: CD150 and CD105. Ten weeks after IR exposure, expression of Sca-1 and c-Kit at the SP cell surface returned to control levels, and BM cellularity of irradiated mice was restored. However, the c-Kit 1 Sca-1 1 Lin 2/low (KSL) stem/progenitor compartment displayed major phenotypic modifications, including an increase and a severe decrease in the frequencies of CD150 1 Flk2 2 and CD150 2 Flk2 1 cells, respectively. CD150 1 KSL cells also showed impaired reconstituting ability, an increased tendency to apoptosis, and accrued DNA damage. Finally, 15 weeks after exposure, irradiated mice, but not agematched controls, allowed engraftment and significant hematopoietic contribution from transplanted congenic HSCs without additional host conditioning. These results provide novel insight in our understanding of immediate and delayed IR-induced hematopoietic injury and highlight similarities between HSCs of young irradiated and old mice.

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Section: The Stem/progenitor Compartment Of Irradiated Mice Resemblessupporting

confidence: 64%

Phenotypic and Functional Changes Induced in Hematopoietic Stem/Progenitor Cells After Gamma-Ray Radiation Exposure

et al. 2009

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“…Mice with defective NHEJ have also revealed the importance of this repair pathway in hematopoietic stem cells as a key determinant in their maintenance and indicate that DNA damage accumulation may be a limiting factor for stem cell renewal (Nijnik et al, 2007;Rossi et al, 2007). Collectively, these mouse models further underscore the critical importance of the DNA DSB repair pathways during mammalian development, and highlight the utility of the mouse as an important biological system for furthering our understanding of DNA repair.…”

Section: Animal Models Of Nhej and Hr Deficienciesmentioning

confidence: 90%

DNA double-strand break repair and development

Phillips

McKinnon

2007

Oncogene

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Normal development of an organism requires the ability to respond to DNA damage. A particularly deleterious lesion is a DNA double-strand break (DSB). The cellular response to DNA DSBs occurs via an integrated sensing and signaling network that maintains genomic stability. The outcomes of defective DNA DSB repair are related to the developmental stage of an organism, and often show striking tissue specificity. Many human diseases are associated with deficiencies in DNA DSB repair and can be characterized by neuropathology, immune deficiency, growth retardation or predisposition to cancer. This review will focus on the requirements of the DNA DSB response that function to maintain homeostasis during mammalian development.

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“…Defects in hematopoietic stem cell (HSC) function were also described in Fancd1, Msh2, and Rad50-deficient mice (Morales et al, 2005;Navarro et al, 2006;Reese et al, 2003). In other recent experiments, Ninjik et al (Nijnik et al, 2007) and Rossi et al (Rossi et al, 2007), examining various DNA repair or telomerase-deficient mouse strains (Lig4, Ku80, Xpd, and mTR), showed that hematopoietic stem cells declined rapidly in functionality with age, if not in number. Moreover, transplantation of mutant HSCs into normal recipient mice resulted in greatly decreased reconstitutive ability in their hosts compared to HSCs derived from normal mice.…”

Section: How Does the Dna Damage Response Affect Tissue Homeostasis?mentioning

confidence: 98%

How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

Hinkal

Donehower

2008

Mechanisms of Ageing and Development

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Long-lived animals have evolved a robust set of defenses to maintain genomic integrity over their entire lifespan. The DNA damage response and DNA repair pathways are critical pillars of organismal defenses, minimizing somatic mutations in both post-mitotic and mitotic cells. These genomic maintenance systems not only prevent the premature emergence of cancers, but may also maintain normal tissue function and organismal longevity. Genetic defects in a number of DNA repair and DNA damage response genes often leads to a dramatic increase in cancer incidence; in other cases, premature aging or progeroid syndromes may be induced. In this review, we discuss two recent reports of two nucleotide excision repair deficient models that exhibit dramatic premature aging and shortened longevity. The DNA repair defects were also associated with a significant inhibition of the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis, an endocrine signaling pathway shown to influence aging and longevity in both vertebrates and invertebrates. Potential mechanisms of how DNA damage might affect IGF-1 signaling and aging are discussed, with a particular emphasis on the role of such signaling alterations in the adult tissue stem cell compartments.

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DNA repair is limiting for haematopoietic stem cells during ageing

Cited by 470 publications

References 42 publications

Phenotypic and Functional Changes Induced in Hematopoietic Stem/Progenitor Cells After Gamma-Ray Radiation Exposure

Phenotypic and Functional Changes Induced in Hematopoietic Stem/Progenitor Cells After Gamma-Ray Radiation Exposure

DNA double-strand break repair and development

How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

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