? The objective of this program is to understand transcriptional regulatory mechanisms that are operative at the G1/S phase cell cycle transition by experimentally addressing control of histone gene expression that is tightly coupled with DNA replication. In studies carried out by this program, we have identified and purified three principal transcription factor complexes that exhibit sequence-specific recognition for the histone H4 gene cell cycle regulatory element designated Site II. HiNF-D is a multimeric complex of the DNA binding protein CDP-cut, pRB, cyclin A and CDKI/CDC2; HiNF-M is the oncoprotein IRF-2; and HiNF-P is a novel zinc-finger DNA binding protein linked to the NPAT/cyclin E/CDK2 cascade. Hence, Site II is a multipartite element that supports responsiveness to diverse physiological signaling pathways. Our central hypothesis is that Site II related regulatory mechanisms support E2F-independent gene activation at a cell cycle transition (S point) that is temporally and functionally distinct from the R point late in G1 and linked to the onset of S phase. Using histone genes as a model, we will combine molecular, biochemical, cellular and in vivo genetic approaches to investigate: (i) the biological role of Site II transcription factors; (ii) integration of Site II related cell cycle signaling pathways; (iii) cell cycle and cell growth dependent remodeling of promoter architecture of the histone H4 gene; and (iv) control of the cell cycle by Site II transcription factors. These studies will elucidate parameters of growth control that mediate competency for proliferation and cell cycle progression. ? ?
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