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Blood, 5 March 2009, Vol. 113, No. 10, pp. 2181-2190.
Prepublished online as a Blood First Edition Paper on December 24, 2008; DOI 10.1182/blood-2008-05-154294.
 Previous Article
Submitted May 2, 2008
Accepted December 2, 2008
ATR-dependent phosphorylation of FANCA on serine 1449 after DNA damage is important for FA pathway function
Natalie B Collins, James B Wilson, Thomas Bush, Andrei Tomashevski, Kate J Roberts, Nigel J Jones, and Gary M Kupfer*
Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA, United States
School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom
Division of Pediatric Hematology-Oncology, Yale University School of Medicine, New Haven, CT, United States
* Corresponding author; email: gary.kupfer{at}yale.edu.
Previous work has shown several proteins defective in Fanconi anemia (FA) are phosphorylated in a functionally critical manner. FANCA is phosphorylated after DNA damage and localized to chromatin, but the site and significance of this phosphorylation are unknown. Mass spectrometry of FANCA revealed one phosphopeptide, phosphorylated on serine 1449. Serine 1449 phosphorylation was induced after DNA damage but not during S phase, in contrast to other post-translational modifications of FA proteins. Furthermore, the S1449A mutant failed to completely correct a variety of FA-associated phenotypes. The DNA damage response is coordinated by phosphorylation events initiated by apical kinases ATM and ATR, and ATR is essential for proper FA pathway function. Serine 1449 is in a consensus ATM/ATR site, phosphorylation in vivo is dependent on ATR, and ATR phosphorylated FANCA on serine 1449 in vitro. Phosphorylation of FANCA on serine 1449 is a DNA damage-specific event that is downstream of ATR and is functionally important in the FA pathway.
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