Geminin (GMNN) tightly binds to CDT1 and inhibits CDT1-mediated loading of the MCM2-7 complex to replication origins. During cell cycle, CDT1 is present only in G1 and S phases, while geminin is present in S and G2 phases. Geminin is thought to prevent inappropriate firing of replication origins during the G2 phase in multicellular eukaryotes (Wohlschlegel et al. 2000).
It has also been proposed that, instead of inhibiting CDT1-mediated loading of the MCM2-7 complex to ORC and CDC6 at the origins of replication, geminin binds to the pre-replicative complex and inhibits its transition to a state competent for initiation of DNA replication (Wu et al. 2014). The study by Wu et al. 2014, however, used recombinant, overexpressed human proteins, and did not take into account cell-cycle regulated expression of CDT1, CDC6 and geminin.
APC/C-dependent degradation of geminin (GMNN) was first demonstrated in Xenopus (McGarry and Kirschner 1998) and was shown to be proteasome-dependent and sensitive to FBXO5 (Emi1)-mediated inhibition of the APC/C:Cdh1 activity in human cells (Machida and Dutta 2007).
NAB2 is recruited to EGR2 to the RRAD promoter through interaction with the NCD1 (NAB conserved domain 1) (Svaren et al, 1996; Svaren et al, 1998). NAB2 in turn recruits the CHD4 subunit of the NURD chromatin remodelling complex through its CID (CHD4-interacting domain) and in this manner, represses transcription from the RRAD promoter (Srinivasan et al, 2006; Mager et al, 2008). In addition to roles in cellular proliferation and cardiac function, RRAD protein is known to contribute to RHO signaling, which promotes Schwann cell migration and myelination (Zhu et al, 1999; Wang et al, 2010; Chang et al, 2007, Ward et al, 2002; Yamauchi et al, 2004; Melendez-Vasquez et al, 2004).