Role of host cell factor-1 in cell cycle regulation

Abstract

Host cell factor-1(HCF-1) was first discovered as a cellular cofactor in the VP16-induced complex, a multi-protein DNA complex that forms on immediate early gene promoters of herpes simplex virus (HSV) to activate viral gene transcription. Subsequent research has revealed HCF-1 to be an abundant chromatin-associated protein that regulates various stages of the cell cycle. Recent reports show that HCF-1 interacts with diverse E2F proteins to induce cell-cycle-specific transcription. HCF-1 can act as a scaffold to a variety of histone-modifying proteins and these HCF-1-E2F-containing multi-protein complexes can bring about context-dependent activation or repression of transcription. In this review we examine the diversity of HCF-E2F interactions and the variety of multi-protein complexes it occurs in, to influence the local chromatin landscape at the E2F-promoters.

Figure 1. Model for E2F-HCF-1 complexes during the cell cycle. This model illustrates the interactions of HCF-1 with various members of E2F family during the cell cycle and the different co-factors associated with them. (A) During early G1 phase, HCF-1 interacts with E2F4 and recruits Sin3 HDAC to E2F-responsive promoters. We speculate that this mechanism of repression is independent of pocket proteins. ANCCA binds to E2F-promoters in late mitosis. However, we do not know if HCF-1 and ANCCA co-occupy these promoters at this time. (B) This model proposes that HCF-1 forms an intermediate complex with pRB-E2F, where pRb has undergone phosphorylation by cyclin D /CDK4 but still remains bound to E2F. As the G1 to S phase transition progresses, this intermediate complex is freed of pRb by subsequent phosphorylation by cyclin/CDK complex thereby switching from repressive (pRb) to activating (HCF-1) E2F-complex.^, (C) Here we speculate the co-factors associated with E2F1 during S phase. ANCCA gets recruited to chromatin by binding to H3K14ac mark. Here it facilitates the loading of E2F to the chromatin. HCF-1 binds to E2F to promote the activation of S-phase genes by recruiting H3K4 HMT (MLL /Set1) and stimulating H3K4 trimethylation of gene promoters. PHF8 binds to H3K4 me2/3 mark and interacts with HCF-1. It removes the repressive H4K20 me1 marks at these promoters. Previous reports have shown that several histone acetyltransferase (HAT) are required for E2F activity.^-