Open AccessHOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin
Author(s) -
Valentina Salsi,
Silvia Ferrari,
Roberta Ferraresi,
Andrea Cossarizza,
Alexis Grande,
Vincenzo Zappavigna
Publication year - 2009
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00509-09
Subject(s) - biology , origin recognition complex , hox gene , dna replication factor cdt1 , dna replication , pre replication complex , control of chromosome duplication , eukaryotic dna replication , microbiology and biotechnology , replication factor c , minichromosome maintenance , licensing factor , genetics , dna , transcription factor , gene
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.