3' processing of pre-mRNA plays a major role in proliferation-dependent regulation of histone gene expression.

A short histone-like fusion RNA, generated when the RNA 3' processing signal from a mouse histone H4 gene is inserted into a heterologous transcription unit, becomes correctly down-regulated in G1-arrested cells of a temperature-sensitive mouse mastocytoma cell cycle mutant (21-Tb; Stauber et al., EMBO J. 5, 3297-3303 [1986]), due to a specific deficiency in histone RNA processing (Lüscher and Schümperli, EMBO J. 6, 1721-1726 [1987]). In contrast, inhibitors of DNA synthesis, known to stimulate histone mRNA degradation, have little or no effect on the fusion RNA. This RNA can therefore be used to discriminate between regulation by RNA 3' processing and RNA stability, respectively. The fusion RNA is also faithfully regulated in 21-Tb cells arrested in G1 phase by the drug indomethacin or in C127 mouse fibroblasts during a serum starvation experiment. Moreover, nuclear extracts from serum-starved C127 cells show a specific deficiency in a heat-labile component of the histone RNA processing apparatus, similar to that previously observed for temperature-arrested 21-Tb cells. These results suggest that RNA 3' processing is a major determinant for the response of histone mRNA levels to changes in cell proliferation.