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  • The EMBO Journal (2007) 26, 1340 - 1351
  • doi:10.1038/sj.emboj.7601574

Published online: 15 February 2007

Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability

Massimo Bogliolo1,a, Alex Lyakhovich1,a, Elsa Callén1, Maria Castellà1, Enrico Cappelli1, María J Ramírez1, Amadeu Creus1, Ricard Marcos1, Reinhard Kalb2, Kornelia Neveling2, Detlev Schindler2 and Jordi Surrallés1,3

  1. Group of Mutagenesis, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
  2. Department of Human Genetics, University of Wurzburg, Wurzburg, Germany
  3. Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Bellaterra, Barcelona, Spain

Correspondence to:

Jordi Surrallés, Department of Genetics and Microbiology, Universitat Autonoma de Barcelona, Campus de Bellaterra, Bellaterra, Barcelona 08193, Spain. Tel.: + 34 93 581 18 30; Fax: + 34 93 581 23 87; E-mail: jordi.surralles@uab.es

aThese authors contributed equally to this work

Received 8 June 2006; Accepted 3 January 2007

Fanconi anemia (FA) is a chromosome fragility syndrome characterized by bone marrow failure and cancer susceptibility. The central FA protein FANCD2 is known to relocate to chromatin upon DNA damage in a poorly understood process. Here, we have induced subnuclear accumulation of DNA damage to prove that histone H2AX is a novel component of the FA/BRCA pathway in response to stalled replication forks. Analyses of cells from H2AX knockout mice or expressing a nonphosphorylable H2AX (H2AXS136A/S139A) indicate that phosphorylated H2AX (gammaH2AX) is required for recruiting FANCD2 to chromatin at stalled replication forks. FANCD2 binding to gammaH2AX is BRCA1-dependent and cells deficient or depleted of H2AX show an FA-like phenotype, including an excess of chromatid-type chromosomal aberrations and hypersensitivity to MMC. This MMC hypersensitivity of H2AX-deficient cells is not further increased by depleting FANCD2, indicating that H2AX and FANCD2 function in the same pathway in response to DNA damage-induced replication blockage. Consequently, histone H2AX is functionally connected to the FA/BRCA pathway to resolve stalled replication forks and prevent chromosome instability.

  • Keywords:

    • BRCA,
    • Fanconi anemia,
    • genome stability,
    • histone H2AX,
    • stalled replication forks