Published online 31 March 2009
Haematologica, Vol 94, Issue 5, 629-637 doi:10.3324/haematol.2008.003327
Copyright © 2009 by Ferrata Storti Foundation
Sharon Noy-Lotan1 ,
Orly Dgany1 ,
Roxane Lahmi1,2 ,
Nathaly Marcoux1 ,
Tanya Krasnov1 ,
Nissan Yissachar2 ,
Doron Ginsberg2 ,
Benny Motro2 ,
Peretz Resnitzky3 ,
Isaac Yaniv5 ,
Gary M. Kupfer4 ,
Hannah Tamary1,5
Haematologica, Vol 94, Issue 5, 629-637 doi:10.3324/haematol.2008.003327
Copyright © 2009 by Ferrata Storti Foundation
Red Cell Disorders |
Codanin-1, the protein encoded by the gene mutated in congenital dyserythropoietic anemia type I (CDAN1), is cell cycle-regulated
1 Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Beilinson Campus, Petah Tiqva
5 Pediatric Hematology Oncology Center, Schneider Children’s Medical Center of Israel, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2 The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Israel
3 Efrati Research Institute for Blood Cells and Cytology, Kaplan Hospital, Rehovot, Israel
4 Division of Pediatric Hematology/Oncology, Yale University School of Medicine, New Haven, USA
Correspondence: Hannah Tamary, MD, Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petah Tiqva 49 202, Israel., E-mail:htamary{at}post.tau.ac.il
Background: Congenital dyserythropoietic anemia type I is an inherited autosomal recessive macrocytic anemia associated with ineffective erythropoiesis and the development of secondary hemochromatosis. Distinct erythroid precursors with internuclear chromatin bridges and spongy heterochromatin are pathognomonic for the disease. The mutated gene (CDAN1) encodes a ubiquitously expressed protein of unknown function, codanin-1. Based on the morphological features of congenital dyserythropoietic anemia type I erythroblasts and data on a role in cell cycle progression of codanin-1 homolog in Drosophila we investigated the cellular localization and possible involvement of codanin-1 during the cell cycle.
Design and Methods: Codanin-1 localization was studied by immunofluorescence and immune electron microscopy. Cell cycle expression of codanin-1 was evaluated using synchronized HeLa cells. E2F proteins are the main regulator of G1/S transition. An E2F1-inducible cell line (U20S-ER-E2F1) enabled us to study codanin-1 expression following ectopic E2F1 induction. Direct binding of E2F1 to codanin-1 promoter was assessed by chromatin immunoprecipitation. We used a luciferase-reporter plasmid to study activation of CDAN1 transcription by E2F1.
Results: We localized codanin-1 to heterochromatin in interphase cells. During the cell cycle, high levels of codanin-1 were observed in the S phase. At mitosis, codanin-1 underwent phosphorylation, which coincided with its exclusion from condensed chromosomes. The proximal CDAN1 gene promoter region, containing five putative E2F binding sites, was found to be a direct target of E2F1.
Conclusions: Taken together, these data suggest that codanin-1 is a cell cycle-regulated protein active in the S phase. The exact role of codanin-1 during the S phase remains to be determined. Nevertheless this represents the first step towards understanding the function of the proteins involved in congenital dyserythropoietic anemia.
Key words: codanin-1, cell cycle, heterochromatin, E2F.
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