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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1003-1009. Prepublished online as a Blood First Edition Paper on September 28, 2004; DOI 10.1182/blood-2003-11-3997. This Article Full Text (PDF) All Versions of this Article: 2003-11-3997v1 105/3/1003    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Montes de Oca, R. Articles by D'Andrea, A. D Search for Related Content PubMed PubMed Citation Articles by Montes de Oca, R. Articles by D'Andrea, A. D Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 21, 2003 Accepted September 9, 2004 Regulated interaction of the Fanconi Anemia protein, FANCD2, with chromatin Rocio Montes de Oca, Paul R Andreassen, Steven P Margossian, Richard G Gregory, Toshiyasu Taniguchi, XiaoZhe Wang, Scott Houghtaling, Markus Grompe, and Alan D D'Andrea* Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Division of Hematology/Oncology, Children's Hospital of Boston, Boston, MA, USA Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, OR, USA * Corresponding author; email: alan_dandrea{at}dfci.harvard.edu. DNA damage activates the monoubiquitination of the Fanconi Anemia protein, FANCD2, resulting in the assembly of FANCD2 nuclear foci. In the current study, we characterize structural features of FANCD2 required for this intranuclear translocation. We have previously identified two normal mRNA splice variants of FANCD2, one containing exon 44 sequence at the 3' end (FANCD2-44) and one containing exon 43 sequence (FANCD2-43). The two predicted FANCD2 proteins differ in their carboxy terminal 24 amino acids. In stably transfected FANCD2(-/-) fibroblasts, FANCD2-44 and FANCD2-43 proteins were monoubiquitinated on K561. Only FANCD2-44 corrected the MMC sensitivity of the transfected cells. We find that monoubiquitinated FANCD2-44 was translocated from the soluble nuclear compartment into chromatin. A mutant form of FANCD2-44 (FANCD2-K561R) was not monoubiquitinated and failed to bind chromatin. A truncated FANCD2 protein (Exon44-T), lacking the carboxy terminal 24 amino acids encoded by exon 44 but retaining K561, and another mutant FANCD2 protein with a single amino acid substitution at a conserved residue within the C-terminal 24 amino acids (D1428A), were monoubiquitinated. Both mutants were targeted to chromatin but failed to correct MMC sensitivity. Taken together, our results indicate that monoubiquitination of FANCD2 regulates chromatin binding and that D1428 within the carboxy terminal acidic sequence encoded by exon 44 is independently required for functional complementation of FA-D2 cells. We hypothesize that the carboxy terminus of FANCD2-44 plays a critical role in sensing or repairing DNA damage. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Bhagwat, A. L. Olsen, A. T. Wang, K. Hanada, P. Stuckert, R. Kanaar, A. D'Andrea, L. J. Niedernhofer, and P. J. 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