Human Origin Recognition Complex Large Subunit Is Degraded by Ubiquitin-Mediated Proteolysis after Initiation of DNA Replication

Abstract

Eukaryotic cells possess overlapping mechanisms to ensure that DNA replication is restricted to the S phase of the cell cycle. The levels of hOrc1p, the largest subunit of the human origin recognition complex, vary during the cell division cycle. In rapidly proliferating cells, hOrc1p is expressed and targeted to chromatin as cells exit mitosis and prereplicative complexes are formed. Later, as cyclin A accumulates and cells enter S phase, hOrc1p is ubiquitinated on chromatin and then degraded. hOrc1p destruction occurs through the proteasome and is signaled in part by the SCF(Skp2) ubiquitin-ligase complex. Other hORC subunits are stable throughout the cell cycle. The regulation of hOrc1p may be an important mechanism in maintaining the ploidy in human cells.

The Emerging Role of the COP9 Signalosome in Cancer

“…[10][11][12]. This function has been proposed to be mediated by the catalytic subunit CSN5 but requires the assembly of the entire CSN holocomplex (10)(11)(12)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). The deneddylation of Cullins is required for Cullin-mediated degradation of E3 substrates.…”

Perpetuating the double helix: molecular machines at eukaryotic DNA replication origins

“…In S. cerevisiae, most replicators are defined by short, specific sequences whereas in higher eukaryotes origin usage is likely dictated by specific chromatin structures that might be epigenetically inherited. (86) Besides, certain regulatory mechanisms appear to have evolved exclusively in metazoa: the dynamic association of mammalian ORC subunit 1 with the chromatin, (87)(88)(89) the role of geminin as an inhibitor of MCM chromatin association, (44,46,47) and the recently discovered role of Ran-GTP and nuclear export factor Crm1 in MCM inactivation. (90) Helicase loading and mode of action The three-dimensional structures of archaeal homologs of Cdc6 and a fragment of MCM protein have recently become available (91,92) and provide interesting insights into their possible functions.…”

The G1 phase E3 ubiquitin ligase TRUSS that gets deregulated in human cancers is a novel substrate of the S-phase E3 ubiquitin ligase Skp2

“…The E3 ubiquitin ligases reportedly play a central role in this process as their deregulation often results in diseased states including cancers. 23 Skp2, which is recognized as the key regulator of c-Myc in the cell, 24 also functions as a cell cycle regulator by controlling the levels of cyclin-dependent kinase inhibitors such as p27, p130, p57 and p21, [25][26][27][28] and replication control protein such as hORC1 and Cdt1, [29][30] Cyclin E 31 and E2F1 32 has been reported differently expressed in several cancers. More recently, Skp2 has been shown to exhibit homeostatic regulation of tumor suppressor DAB2IP and suppression of JARID1B demethylase activity in prostate carcimona.…”