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 Blood, 2 July 2009, Vol. 114, No. 1, pp. 174-180.
Prepublished online as a Blood First Edition Paper on May 7, 2009; DOI 10.1182/blood-2009-02-207811.

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Submitted February 26, 2009
Accepted April 22, 2009

Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M

Thiyam Ramsing Singh, Sietske T. Bakker, Sheba Agarwal, Michael Jansen, Elke Grassman, Barbara C. Godthelp, Abdullah Mahmood Ali, Chang-hu Du, Martin A. Rooimans, Qiang Fan, Kebola Wahengbam, Jurgen Steltenpool, Paul R. Andreassen, David A. Williams, Hans Joenje, Johan P. de Winter*, and Amom Ruhikanta Meetei

Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, United States
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands
Department of Clinical Genetics, VU University Medical Centre, Amsterdam, Netherlands
Department of Toxicogenetics, Leiden University Medical Center, Leiden, Netherlands

* Corresponding author; email: j.dewinter{at}vumc.nl.

FANCM is a component of the Fanconi anemia (FA) core complex and one FA patient (EUFA867) with biallelic mutations in FANCM has been described. Strikingly, we found that EUFA867 also carries biallelic mutations in FANCA. After correcting the FANCA defect in EUFA867 lymphoblasts, a 'clean' FA-M cell line was generated. These cells were hypersensitive to mitomycin C, but unlike cells defective in other core complex members, FANCM-/- cells were proficient in monoubiquitinating FANCD2 and were sensitive to the topoisomerase inhibitor camptothecin, a feature shared only with the FA subtype D1 and N. In addition, FANCM-/- cells were sensitive to UV light. FANCM and a C-terminal deletion mutant rescued the crosslinker sensitivity of FANCM-/- cells, while a FANCM ATPase mutant did not. Since both mutants restored the formation of FANCD2 foci we conclude that FANCM functions in an FA core complex dependent and independent manner.


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