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  • The EMBO Journal (2005) 24, 861 - 871
  • doi:10.1038/sj.emboj.7600542

Published online: 3 February 2005

Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1-/- mice

Joanna M Prasher1,a, Astrid S Lalai2,a, Claudia Heijmans-Antonissen1, Robert E Ploemacher1, Jan HJ Hoeijmakers2, Ivo P Touw1 and Laura J Niedernhofer2,b

  1. Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands
  2. Department of Cell Biology and Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

Correspondence to:

Ivo P Touw, Department of Hematology, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands. Tel.: +31 1040 87837; Fax: +31 1040 89470; E-mail: i.touw@erasmusmc.nl

aThese authors contributed equally to this work

bPresent address: Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA

Received 2 July 2004; Accepted 10 December 2004

The ERCC1-XPF heterodimer is a structure-specific endonuclease involved in both nucleotide excision repair and interstrand crosslink repair. Mice carrying a genetic defect in Ercc1 display symptoms suggestive of a progressive, segmental progeria, indicating that disruption of one or both of these DNA damage repair pathways accelerates aging. In the hematopoietic system, there are defined age-associated changes for which the cause is unknown. To determine if DNA repair is critical to prolonged hematopoietic function, hematopoiesis in Ercc1-/- mice was compared to that in young and old wild-type mice. Ercc1-/- mice (3-week-old) exhibited multilineage cytopenia and fatty replacement of bone marrow, similar to old wild-type mice. In addition, the proliferative reserves of hematopoietic progenitors and stress erythropoiesis were significantly reduced in Ercc1-/- mice compared to age-matched controls. These features were not seen in nucleotide excision repair-deficient Xpa-/- mice, but are characteristic of Fanconi anemia, a human cancer syndrome caused by defects in interstrand crosslink repair. These data support the hypothesis that spontaneous interstrand crosslink damage contributes to the functional decline of the hematopoietic system associated with aging.

  • Keywords:

    • Fanconi anemia,
    • hematopoietic progenitors,
    • nucleotide excision repair,
    • progeria,
    • senescence