Homeotic proteins participate in the function of human-DNA replication origins

Abstract

Recent evidence points to homeotic proteins as actors in the crosstalk between development and DNA replication. The present work demonstrates that HOXC13, previously identified as a new member of human DNA replicative complexes, is a stable component of early replicating chromatin in living cells: it displays a slow nuclear dynamics due to its anchoring to the DNA minor groove via the arginine-5 residue of the homeodomain. HOXC13 binds in vivo to the lamin B2 origin in a cell-cycle-dependent manner consistent with origin function; the interaction maps with nucleotide precision within the replicative complex. HOXC13 displays in vitro affinity for other replicative complex proteins; it interacts also in vivo with the same proteins in a cell-cycle-dependent fashion. Chromatin-structure modifying treatments, disturbing origin function, reduce also HOXC13–origin interaction. The described interactions are not restricted to a single origin nor to a single homeotic protein (also HOXC10 binds the lamin B2 origin in vivo). Thus, HOX complexes probably contribute in a general, structure-dependent manner, to origin identification and assembly of replicative complexes thereon, in presence of specific chromatin configurations.

Cellular and molecular insights into Hox protein action

“…Several Hox proteins stimulate pre-replication complex assembly and DNA replication. They associate with replication origins and interact with geminin, an inhibitor of replication licensing, as well as with licensing factors (Comelli et al, 2009;Luo et al, 2004;Marchetti et al, 2010;Salsi et al, 2009). DNA repair.…”

DNA-protein interaction dynamics at the Lamin B2 replication origin

“…This justifies both the presence of transcription factor binding sites in close proximity to origins and the well established connection between origin location and the transcriptional activity and chromatin conformation of the regions where origins are positioned [9][10][11][12] . Indeed, transcription factor-induced remodeling of chromatin towards an accessible state is believed to be a key regulatory element determining pre-RC assembly at origins 13,14 .…”

Using wavelet-transform to detecting of origin of replication in human DNA

“…Это последовательности Orc-HCO5, Orc-HCO8, Orc-HCO13, Orc-HCO14, Orc-HCO15 (приложение 3, рис. [26][27][28][29][30].…”

“…Вопросам синхронизации репликации с фазами клеточного цикла, изучению ее роли в развитии, связи с HOX-белками [29], регуляции процесса репликации и ее нарушениям, в частности, при канцерогенезе [30,31] уделяется огромное внимание.…”