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Nucleic Acids Research Advance Access originally published online on January 7, 2009
Nucleic Acids Research 2009 37(6):1740-1754; doi:10.1093/nar/gkn995
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Nucleic Acids Research, 2009, Vol. 37, No. 6 1740-1754
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome Integrity, Repair and Replication

A role for monoubiquitinated FANCD2 at telomeres in ALT cells

Qiang Fan1, Fan Zhang1, Briana Barrett2, Keqin Ren1 and Paul R. Andreassen1,*

1Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229 and 2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA

*To whom correspondence should be addressed. Tel: +1 513 636 0499; Fax: +1 513 803 0783; Email: paul.andreassen{at}cchmc.org

Received September 30, 2008. Revised November 13, 2008. Accepted November 25, 2008.

Both Fanconi anemia (FA) and telomere dysfunction are associated with chromosome instability and an increased risk of cancer. Because of these similarities, we have investigated whether there is a relationship between the FA protein, FANCD2 and telomeres. We find that FANCD2 nuclear foci colocalize with telomeres and PML bodies in immortalized telomerase-negative cells. These cells maintain telomeres by alternative lengthening of telomeres (ALT). In contrast, FANCD2 does not colocalize with telomeres or PML bodies in cells which express telomerase. Using a siRNA approach we find that FANCA and FANCL, which are components of the FA nuclear core complex, regulate FANCD2 monoubiquitination and the telomeric localization of FANCD2 in ALT cells. Transient depletion of FANCD2, or FANCA, results in a dramatic loss of detectable telomeres in ALT cells but not in telomerase-expressing cells. Furthermore, telomere loss following depletion of these proteins in ALT cells is associated with decreased homologous recombination between telomeres (T-SCE). Thus, the FA pathway has a novel function in ALT telomere maintenance related to DNA repair. ALT telomere maintenance is therefore one mechanism by which monoubiquitinated FANCD2 may promote genetic stability.


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