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Human Molecular Genetics Advance Access published online on February 19, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn054
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Published by Oxford University Press 2008

FANCM of the Fanconi anemia core complex is required for both monoubiquitination and DNA repair

Yutong Xue, Yongjiang Li, Rong Guo, Chen Ling and Weidong Wang*

Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 333 Cassell Drive, TRIAD Center Room 3000, Baltimore, Maryland 21224

* Corresponding author. Corresponding author contact information: Address: Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 333 Cassell Drive, TRIAD Center Room 3000, Baltimore, Maryland 21224. Telephone: 410-558-8334 Fax: 410-558-8331 Email: wangw{at}grc.nia.nih.gov

Received January 3, 2008; Revised February 15, 2008; Accepted February 15, 2008

In response to DNA damage, the Fanconi anemia (FA) core complex functions as a signaling machine for monoubiquitination of FANCD2 and FANCI. It remains unclear whether this complex can also participate in subsequent DNA repair. We have previously shown that the FANCM constituent of the complex contains a highly conserved helicase domain and an associated ATP-dependent DNA translocase activity. Here we show that FANCM also possesses an ATP-independent binding activity and an ATP-dependent bi-directional branch-point translocation activity on a synthetic four-way junction DNA, which mimics intermediates generated during homologous recombination or at stalled replication forks. Using an siRNA-based complementation system, we found that the ATP-dependent activities of FANCM are required for cellular resistance to a DNA crosslinking drug, mitomycin C (MMC), but not for the monoubiquitination of FANCD2 and FANCI. In contrast, monoubiquitination requires the entire helicase domain of FANCM, which has both ATP- dependent and independent activities. These data are consistent with participation of FANCM and its associated FA core complex in the FA pathway at both signaling through monoubiquitination and the ensuing DNA repair.


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