Evidence for complete epistasis of null mutations in murine Fanconi anemia genes Fanca and Fancg

Henri J. Van de Vrugt, Mireille Koomen, Sietske Bakker, Mariska A D Berns, Ngan Ching Cheng, Martin A. van der Valk, Yne de Vries, Martin A. Rooimans, Anneke B. Oostra, Maureen Hoatlin, Hein te Riele, Hans Joenje, Fré Arwert

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Fanconi anemia (FA) is a heritable disease characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. The 15 identified FA genes operate in a molecular pathway to preserve genomic integrity. Within this pathway the FA core complex operates as an ubiquitin ligase that activates the complex of FANCD2 and FANCI to coordinate DNA repair. The FA core complex is formed by at least 12 proteins. However, only the FANCL subunit displays ubiquitin ligase activity. FANCA and FANCG are members of the FA core complex for which no other functions have been described than to participate in protein interactions. In this study we generated mice with combined null alleles for Fanca and Fancg to identify extended functions for these genes by characterizing the double mutant mice and cells.Double mutant a -/-/g -/- mice were born at near Mendelian frequencies without apparent developmental abnormalities. Histological analysis of a -/-/g -/- mice revealed a Leydig cell hyperplasia and frequent vacuolization of Sertoli cells in testes, while ovaries were depleted from developing follicles and displayed an interstitial cell hyperplasia. These gonadal aberrations were associated with a compromised fertility of a -/-/g -/- males and females. During the first year of life a -/-/g -/- did not develop malignancies or bone marrow failure. At the cellular level a -/-/g -/-, Fanca -/-, and Fancg -/- cells proved equally compromised in DNA crosslink and homology-directed repair. Overall the phenotype of a -/-/g -/- double knockout mice and cells appeared highly similar to the phenotype of Fanca or Fancg single knockouts. The lack of an augmented phenotype suggest that null mutations in Fanca or Fancg are fully epistatic, making additional important functions outside of the FA core complex highly unlikely.

Original languageEnglish (US)
Pages (from-to)1252-1261
Number of pages10
JournalDNA Repair
Volume10
Issue number12
DOIs
StatePublished - Dec 10 2011

Fingerprint

Fanconi Anemia
Genes
Ligases
Ubiquitin
Mutation
Bone
Repair
DNA
Aberrations
Phenotype
Hyperplasia
Proteins
Bone Marrow Diseases
Display devices
Leydig Cells
Sertoli Cells
Knockout Mice
DNA Repair
Fertility
Testis

Keywords

  • Crosslink repair
  • Fanca
  • Fancg
  • Fanconi anemia
  • Knockout mice

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Van de Vrugt, H. J., Koomen, M., Bakker, S., Berns, M. A. D., Cheng, N. C., van der Valk, M. A., ... Arwert, F. (2011). Evidence for complete epistasis of null mutations in murine Fanconi anemia genes Fanca and Fancg. DNA Repair, 10(12), 1252-1261. https://doi.org/10.1016/j.dnarep.2011.09.015

Evidence for complete epistasis of null mutations in murine Fanconi anemia genes Fanca and Fancg. / Van de Vrugt, Henri J.; Koomen, Mireille; Bakker, Sietske; Berns, Mariska A D; Cheng, Ngan Ching; van der Valk, Martin A.; de Vries, Yne; Rooimans, Martin A.; Oostra, Anneke B.; Hoatlin, Maureen; te Riele, Hein; Joenje, Hans; Arwert, Fré.

In: DNA Repair, Vol. 10, No. 12, 10.12.2011, p. 1252-1261.

Research output: Contribution to journalArticle

Van de Vrugt, HJ, Koomen, M, Bakker, S, Berns, MAD, Cheng, NC, van der Valk, MA, de Vries, Y, Rooimans, MA, Oostra, AB, Hoatlin, M, te Riele, H, Joenje, H & Arwert, F 2011, 'Evidence for complete epistasis of null mutations in murine Fanconi anemia genes Fanca and Fancg', DNA Repair, vol. 10, no. 12, pp. 1252-1261. https://doi.org/10.1016/j.dnarep.2011.09.015
Van de Vrugt HJ, Koomen M, Bakker S, Berns MAD, Cheng NC, van der Valk MA et al. Evidence for complete epistasis of null mutations in murine Fanconi anemia genes Fanca and Fancg. DNA Repair. 2011 Dec 10;10(12):1252-1261. https://doi.org/10.1016/j.dnarep.2011.09.015
Van de Vrugt, Henri J. ; Koomen, Mireille ; Bakker, Sietske ; Berns, Mariska A D ; Cheng, Ngan Ching ; van der Valk, Martin A. ; de Vries, Yne ; Rooimans, Martin A. ; Oostra, Anneke B. ; Hoatlin, Maureen ; te Riele, Hein ; Joenje, Hans ; Arwert, Fré. / Evidence for complete epistasis of null mutations in murine Fanconi anemia genes Fanca and Fancg. In: DNA Repair. 2011 ; Vol. 10, No. 12. pp. 1252-1261.
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AU - Cheng, Ngan Ching

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