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Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability
Author(s) -
Bogliolo Massimo,
Lyakhovich Alex,
Callén Elsa,
Castellà Maria,
Cappelli Enrico,
Ramírez María J,
Creus Amadeu,
Marcos Ricard,
Kalb Reinhard,
Neveling Kornelia,
Schindler Detlev,
Surrallés Jordi
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601574
Subject(s) - biology , fancd2 , fanconi anemia , chromatin , dna damage , dna repair , bloom syndrome , chromosome instability , histone , dna replication , microbiology and biotechnology , chromatid , genetics , chromosome , dna , gene , helicase , rna
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 (γH2AX) is required for recruiting FANCD2 to chromatin at stalled replication forks. FANCD2 binding to γH2AX 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.