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RESEARCH COMMUNICATION
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
Fanconi anemia (FA) is a multigenic autosomal recessive cancer susceptibility syndrome. The FA pathway regulates the monoubiquitination of FANCD2 and the assembly of damage-associated FANCD2 nuclear foci. How FANCD2 monoubiquitination is coupled to the DNA-damage response has remained undetermined. Here, we demonstrate that the ATR checkpoint kinase and RPA1 are required for efficient FANCD2 monoubiquitination. Deficiency of ATR function, either in Seckel syndrome, which clinically resembles Fanconi anemia, or by siRNA silencing, results in the formation of radial chromosomes in response to the DNA cross-linker, mitomycin C (MMC), thus mimicking the chromosome instability of FA cells.
[Keywords: Fanconi anemia; FANCD2; cancer susceptibility; checkpoint; replication stress]
Received February 20, 2004; revised version accepted June 11, 2004.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1196104.
1 Corresponding author.
E-MAIL alan_dandrea{at}dfci.harvard.edu; FAX (617) 632-5757.
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