Investigating the molecular mechanisms that underpin SLBP function and histone mRNA metabolism during S phase of the cell cycle

During DNA replication, newly replicated DNA strands associate with histone proteins in order to condense and form chromatin. The rate of DNA replication and the rate of histone protein synthesis are tightly coupled to maintain genomic integrity. Under conditions of replication stress, replication forks slow or stall and the intra-S phase checkpoint is activated. At the same time, histone mRNA is rapidly degraded by the histone mRNA decay pathway to inhibit the production of new histones. Müller et al. (2007) previously demonstrated that activated checkpoint sensors are required to initiate histone mRNA decay, however, the precise molecular mechanisms that link activated intra-S phase checkpoint signalling and histone mRNA decay are not clear. Recent evidence from the Smythe group suggests that residues in the N-terminus of stem-loop binding protein (SLBP), the master regulator of histone mRNA metabolism, are phosphorylated in response to hydroxyurea-induced replication stress and may be involved in the initiation of histone mRNA decay by promoting the dissociation of SLBP and histone mRNA. In data presented here, it is shown that phosphorylation of S20 and S23 does not regulate histone mRNA decay. Furthermore, the identification and characterisation of an evolutionarily conserved, multifunctional short linear motif (SLiM) in SLBP revealed an important association between residues within the SLiM and S23 that is required for the expression of histone genes in S phase.