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J. Biol. Chem., Vol. 283, Issue 15, 9844-9851, April 11, 2008

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Tip60 Is Required for DNA Interstrand Cross-link Repair in the Fanconi Anemia Pathway^*

From the Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon 97239

The disease Fanconi anemia is a genome instability syndrome characterized by cellular sensitivity to DNA interstrand cross-linking agents, manifest by decreased cellular survival and chromosomal aberrations after such treatment. There are at least 13 proteins acting in the pathway, with the FANCD2 protein apparently functioning as a late term effecter in the maintenance of genome stability. We find that the chromatin remodeling protein, Tip60, interacts directly with the FANCD2 protein in a yeast two-hybrid system. This interaction has been confirmed by co-immunoprecipitation and co-localization using both endogenous and epitope-tagged FANCD2 and Tip60 from human cells. The observation of decreased cellular survival after exposure to mitomycin C in normal fibroblasts depleted for Tip60 indicates a direct function in interstrand cross-link repair. The coincident function of Tip60 and FANCD2 in one pathway is supported by the finding that depletion of Tip60 in Fanconi anemia cells does not increase sensitivity to DNA cross-links. However, depletion of Tip60 did not reduce monoubiquitination of FANCD2 or its localization to nuclear foci following DNA damage. The observations indicate that Fanconi anemia proteins act in concert with chromatin remodeling functions to maintain genome stability after DNA cross-link damage.

Received for publication, November 6, 2007 , and in revised form, February 5, 2008.

^* This work was supported by NHLBI, National Institutes of Health Program Project Grant 1PO1HL48546 and Northwest Health Foundation Grant 2001-218. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: L-103, Dept. of Molecular and Medical Genetics, OHSU, 3181 Sam Jackson Parkway, Portland, OR 97239. Tel.: 503-494-6881; Fax: 503-494-6882; E-mail: mosesr{at}ohsu.edu.

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