Functional interplay between histone H3 lysine 4 methylation and 3' end formation in yeast — University of Technology
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Functional interplay between histone H3 lysine 4 methylation and 3' end formation in yeast

Functional interplay between histone H3 lysine 4 methylation and 3' end formation in yeast

Melissa Curtis1, Thanasis Margaritis2, Frank Holstege2, Traude Beilharz3 and Bernhard Dichtl1,4

1Centre for Cellular and Molecular Biology, Deakin University, Melbourne, Australia

2Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands.

3Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia.

4presenting author

Pre-mRNA 3’ end formation entails endonucleolytic cleavage of the nascent RNA followed by poly(A) addition. Despite the simplicity of this biochemical process 3’ end formation factors are constituted by more than twenty different polypeptides in yeast. The role for many of those proteins remains unclear and few biological functions have been attributed to those factors. Intriguingly, the Swd2 component of Cleavage and Polyadenylation factor CPF is shared with the histone H3 lysine 4 (H3K4) methyltransferase SET1C. We observed that mutants deficient for H3K4 methylation, were resistant to the microtuble destabilizing drug Benomyl, and this phenotype was suppressed by mutations within Swd2 and deletion of the CPF component Ref2. Similarly, mutations in poly(A) polymerase and its interacting protein Fip1 displayed Benomyl resistance while the absence of the major 5’-3’ exonuclease Xrn1 resulted in Benomyl sensitivity. Gene expression analyses of set1 mutants in alpha factor synchronised cells revealed down regulation of tubulin subunits, up-regulation of certain kinetochore subunits and miss-regulation of other gene products involved in chromosome segregation. Our results support the view that microtuble stability is subject to complex regulation involving H3K4 methylation and pre-mRNA processing. In addition, Glc7 phosphatase is associated with CPF and is known to act as important regulator of the microtuble-kintochore association (Sasson et al, Genes Dev. 1999, 13(5):545-55). Taken together, the 3’end formation machinery appears to act as integration hub during the cell-cycle to coordinate RNA processing, upstream gene transcription, and downstream post-translational processes.