Nature Genetics
35, 165 - 170 (2003)
Published online: 14 September 2003; | doi:10.1038/ng1241
A novel ubiquitin ligase is deficient in Fanconi anemiaAmom Ruhikanta Meetei1, Johan P de Winter2, Annette L Medhurst2, Michael Wallisch3, Quinten Waisfisz2, Henri J van de Vrugt2, Anneke B Oostra2, Zhijiang Yan1, Chen Ling1, Colin E Bishop4, Maureen E Hoatlin3, Hans Joenje2
& Weidong Wang11
Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 333 Cassell Drive, TRIAD Center Room 3000, Baltimore, Maryland 21224, USA. 2
Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands. 3
Division of Molecular Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. 4
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030, USA.
Correspondence should be addressed to Weidong Wang wangw@grc.nia.nih.govFanconi anemia is a recessively inherited disease characterized by congenital defects, bone marrow failure and cancer susceptibility1,
2. Cells from individuals with Fanconi anemia are highly sensitive to DNA-crosslinking drugs, such as mitomycin C (MMC). Fanconi anemia proteins function in a DNA damage response pathway involving breast cancer susceptibility gene products, BRCA1 and BRCA2 (refs. 1,2). A key step in this pathway is monoubiquitination of FANCD2, resulting in the redistribution of FANCD2 to nuclear foci containing BRCA1 (ref. 3). The underlying mechanism is unclear because the five Fanconi anemia proteins known to be required for this ubiquitination have no recognizable ubiquitin ligase motifs. Here we report a new component of a Fanconi anemia protein complex, called PHF9, which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo. Because PHF9 is defective in a cell line derived from an individual with Fanconi anemia, we conclude that PHF9 (also called FANCL) represents a novel Fanconi anemia complementation group (FA-L). Our data suggest that PHF9 has a crucial role in the Fanconi anemia pathway as the likely catalytic subunit required for monoubiquitination of FANCD2.
|
