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Molecular and Cellular Biology, November 2009, p. 5775-5788, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00509-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin{triangledown} ,{ddagger}

Valentina Salsi,1,{dagger} Silvia Ferrari,1,{dagger} Roberta Ferraresi,2 Andrea Cossarizza,2 Alexis Grande,2 and Vincenzo Zappavigna1*

Department of Animal Biology,1 Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via G. Campi 213/d, Modena 41100, Italy2

Received 20 April 2009/ Returned for modification 26 May 2009/ Accepted 12 August 2009

HOX DNA-binding proteins control patterning during development by regulating processes such as cell aggregation and proliferation. Recently, a possible involvement of HOX proteins in replication origin activity was suggested by results showing that a number of HOX proteins interact with the DNA replication licensing regulator geminin and bind a characterized human origin of replication. The functional significance of these observations, however, remained unclear. We show that HOXD13, HOXD11, and HOXA13 bind in vivo all characterized human replication origins tested. We furthermore show that HOXD13 interacts with the CDC6 loading factor, promotes pre-replication complex (pre-RC) proteins assembly at origins, and stimulates DNA synthesis in an in vivo replication assay. HOXD13 expression in cultured cells accelerates DNA synthesis initiation in correlation with the earlier pre-RC recruitment onto origins during G1 phase. Geminin, which interacts with HOXD13 as well, blocks HOXD13-mediated assembly of pre-RC proteins and inhibits HOXD13-induced DNA replication. Our results uncover a function for Hox proteins in the regulation of replication origin activity and reveal an unforeseen role for the inhibition of HOX protein activity by geminin in the context of replication origin licensing.

* Corresponding author. Mailing address: Department of Animal Biology, University of Modena and Reggio Emilia, Via G. Campi 213/d, Modena 41100, Italy. Phone: 39 059 2055537. Fax: 39 059 2055548. E-mail: zappavigna.vincenzo{at}unimore.it

{triangledown} Published ahead of print on 24 August 2009.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} V.S. and S.F. contributed equally to this study.

Molecular and Cellular Biology, November 2009, p. 5775-5788, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00509-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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