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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 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 Citation Map 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. Related Collections Hematopoiesis and Stem Cells Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Regulated interaction of the Fanconi anemia protein, FANCD2, with chromatin Rocio Montes de Oca, Paul R. Andreassen, Steven P. Margossian, Richard C. Gregory, Toshiyasu Taniguchi, XiaoZhe Wang, Scott Houghtaling, Markus Grompe, and Alan D. D'Andrea From the Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Division of Hematology/Oncology, Children's Hospital of Boston, Boston, MA; and Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, OR. DNA damage activates the monoubiquitination of the Fanconi anemia (FA) 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 2 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 2 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 mitomycin C (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: J. M. Kim, Y. Kee, A. Gurtan, and A. D. D'Andrea Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24 Blood, May 15, 2008; 111(10): 5215 - 5222. [Abstract] [Full Text] [PDF] J. Hejna, M. Holtorf, J. Hines, L. Mathewson, A. Hemphill, M. Al-Dhalimy, S. B. Olson, and R. E. Moses Tip60 Is Required for DNA Interstrand Cross-link Repair in the Fanconi Anemia Pathway J. Biol. 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[Abstract] [Full Text] [PDF] G. P. H. Ho, S. Margossian, T. Taniguchi, and A. D. D'Andrea Phosphorylation of FANCD2 on Two Novel Sites Is Required for Mitomycin C Resistance. Mol. Cell. Biol., September 1, 2006; 26(18): 7005 - 7015. [Abstract] [Full Text] [PDF] E. Barroso, R.L. Milne, L.P. Fernandez, P. Zamora, J.I. Arias, J. Benitez, and G. Ribas FANCD2 associated with sporadic breast cancer risk Carcinogenesis, September 1, 2006; 27(9): 1930 - 1937. [Abstract] [Full Text] [PDF] H. Kitao, K. Yamamoto, N. Matsushita, M. Ohzeki, M. Ishiai, and M. Takata Functional Interplay between BRCA2/FancD1 and FancC in DNA Repair J. Biol. Chem., July 28, 2006; 281(30): 21312 - 21320. [Abstract] [Full Text] [PDF] X. Yu, S. Fu, M. Lai, R. Baer, and J. Chen BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes & Dev., July 1, 2006; 20(13): 1721 - 1726. [Abstract] [Full Text] [PDF] T. Taniguchi and A. D. D'Andrea Molecular pathogenesis of Fanconi anemia: recent progress Blood, June 1, 2006; 107(11): 4223 - 4233. [Abstract] [Full Text] [PDF] A. Sobeck, S. Stone, V. Costanzo, B. de Graaf, T. Reuter, J. de Winter, M. Wallisch, Y. Akkari, S. Olson, W. Wang, et al. Fanconi Anemia Proteins Are Required To Prevent Accumulation of Replication-Associated DNA Double-Strand Breaks Mol. Cell. Biol., January 15, 2006; 26(2): 425 - 437. [Abstract] [Full Text] [PDF] S. P. Margossian, G. Ho, R. Kennedy, and A. D. D'Andrea Functional Interaction between FANCD2 and ATM in the DNA Damage Response. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 181 - 181. [Abstract] H. Ishii, T. Inageta, K. Mimori, T. Saito, H. Sasaki, M. Isobe, M. Mori, C. M. Croce, K. Huebner, K. Ozawa, et al. Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis PNAS, July 5, 2005; 102(27): 9655 - 9660. [Abstract] [Full Text] [PDF] W.-H. Park, S. 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