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Review
. 2013 Jun 11;33(3):e00044.
doi: 10.1042/BSR20130036.

The origin recognition complex in human diseases

Zhen Shen  1
Affiliations
Review

The origin recognition complex in human diseases

Zhen Shen. Biosci Rep. .

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.

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Figures

Figure 1
Figure 1. Orc1 mutations in MGS
Missense mutations E127G and R105Q occur within the BAH domain as well as the CID. The Orc1 BAH domain binds to H4K20me2, which is important for ORC chromatin association, DNA replication and cell-cycle progression. On the other hand, the R105Q mutation in the CID can specifically abolish Orc1 inhibition of cyclin E-CDK2 kinase, and ectopically expressing this mutant causes reduplication of centrioles/centrosomes and slower cell proliferation. Therefore Orc1 deregulation from both cellular pathways lead to reduced and insufficient cell growth, which could be one major cause of MGS.
Figure 2
Figure 2. Replication initiation machinery in Trypanosoma brucei
Besides the well-characterized TbOrc1/Cdc6, novel components like the Orc4 orthologue, Orc1-like protein Orc1b and new factors Tb7980 and Tb3120 have been described, although the underlying molecular mechanism of how they function in replication initiation remains to be elucidated. It is also possible that other ORC homologues or unknown factors exist (depicted in grey colour) to facilitate the replication. Many of these features could be potentially exploited as therapeutic targets (blue arrowheads), including: (i) the archaeal-like ATPase activities in TbOrc1/Cdc6, TbOrc1b and TbOrc4 (illustrated as ‘A’ in the circle); (ii) novel factors Tb7980 and Tb3120 that lack conserved AAA+ ATPases motifs; (iii) yet-to-identify factors facilitating TbORC functions; and (iv) the role of TbOrc1/Cdc6 in controlling VSG switching.
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