The origin recognition complex in human diseases

Abstract

ORC (origin recognition complex) serves as the initiator for the assembly of the pre-RC (pre-replication complex) and the subsequent DNA replication. Together with many of its non-replication functions, ORC is a pivotal regulator of various cellular processes. Notably, a number of reports connect ORC to numerous human diseases, including MGS (Meier–Gorlin syndrome), EBV (Epstein–Barr virus)-infected diseases, American trypanosomiasis and African trypanosomiasis. However, much of the underlying molecular mechanism remains unclear. In those genetic diseases, mutations in ORC alter its function and lead to the dysregulated phenotypes; whereas in some pathogen-induced symptoms, host ORC and archaeal-like ORC are exploited by these organisms to maintain their own genomes. In this review, I provide detailed examples of ORC-related human diseases, and summarize the current findings on how ORC is involved and/or dysregulated. I further discuss how these discoveries can be generalized as model systems, which can then be applied to elucidating other related diseases and revealing potential targets for developing effective therapies.

HsOrc4-dependent DNA remodeling of the ori-β DHFR replicator

“…The protein HsOrc4 is essential for the organism, with very few viable ORC mutations detected. Mutations in the Orc4 subunit are detected in human disorders [29][30][31], but the exact function of this subunit is as-yet unknown. We suggest that Orc4 plays a crucial role in ORC-DNA interaction.…”

Epstein - Barr virus Reactivation Associated with an Increased Thymidine Kinase and Normalized by an Immuno Modulatory Nano-Therapy: Three Case Reports

“…Studies in this sense have already been carried out within the limited scope of work on the origin recognition complex and demonstrating how EBV uses its own genes to initiate its replicative machinery [7]. Moreover, at the clinical level, the causal role played by EBV has been demonstrated, in connection with other viral factors and immune disorders involved in the etiopathogenesis of systemic lupus erythematosus [8].…”

Nuclear DNA replication and repair in parasites of the genusLeishmania: Exploiting differences to develop innovative therapeutic approaches

“…This feature is reminiscent of archaea organization (Barry & Bell, 2006;Godoy et al, 2009;Kumar et al, 2008). Indeed, most archaea genomes contain at least one gene with similarity to both ORC1 and CDC6 genes, although exceptions are found in some methanogenic species (reviewed by Barry & Bell, 2006;Shen, 2013). In T. brucei and T. cruzi, ORC1/CDC6 is expressed throughout the cell cycle.…”

“…(Table 1; Shen, 2013;Tiengwe et al, 2012b). These genes have been identified as divergent homologs of ORC4.…”

“…homology searches, and ORC4, Tb3120 and Tb7980 (Shen, 2013;Tiengwe et al, 2012b) by affinity purification. Through additional phylogenetic analyses, McCulloch et al (Tiengwe et al, 2012b) concluded that Tb927.10.13380 from T. brucei encodes a divergent orthologue of the eukaryotic ORC4 subunit.…”