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

  • EMBO J. 2007 Mar 7;26(5):1340-51. doi: 10.1038/sj.emboj.7601574.
Massimo Bogliolo  1 ,  Alex Lyakhovich ,  Elsa Callén ,  Maria Castellà ,  Enrico Cappelli ,  María J Ramírez ,  Amadeu Creus ,  Ricard Marcos ,  Reinhard Kalb ,  Kornelia Neveling ,  Detlev Schindler ,  Jordi Surrallés
Affiliations
  • 1. Group of Mutagenesis, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
PMID: 17304220 DOI: 10.1038/sj.emboj.7601574
Abstract

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 (H2AX(S136A/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.