RNA

While studying the late flowering Arabidopsis mutants fca, fy and fpa, we discovered that the proteins encoded by the genes disrupted in these mutants control mRNA poly(A) site selection. This has led us to study alternative polyadenylation and transcription termination.

FCA is a plant-specific RNA binding protein comprising two RRMs and a protein interaction WW domain. FCA physically interacts with FY through this WW domain and this is essential for the function FCA performs in flowering time control. FY encodes a protein that is highly conserved in eukaryotes and is required for cleavage and polyadenylation. It corresponds to the yeast protein Pfs2p and the recently identified component of human CPSF, WDR33. Viable mutants of FY are late flowering, but null alleles are lethal. FCA promotes proximal poly(A) site selection and requires the interaction with FY to do this. We have now discovered that FPA, an RNA binding protein comprising three RRMs, also controls poly(A) site selection, but in a genetically independent manner from FCA.

Alternative polyadenylation is a surprisingly common form of gene regulation. However, it has been studied in detail at only a few loci, so we know relatively little about the mechanisms involved. What is unique about our work is that we have identified two trans-acting regulators of alternative polyadenylation. We have great experimental advantages here, as we have a genetically tractable system to work with dependent on quantitative changes in gene expression.

We are determining the mechanism by which FCA and FPA promote poly(A) site selection. In addition, we are using different genetic backgrounds to guide bioinformatic analysis of next generation sequence data to identify genome-wide changes in alternative polyadenylation.

We are studying how proteins related to Arabidopsis FY and FPA function in humans in collaboration with colleagues in the College of Life Sciences. In this way, we can rapidly translate findings gained from the genetic analysis of flowering to knowledge relevant to medicine.