Abstract
Attenuation of RAS/RAF/MAPK signalling is essential to prevent hyperactivation of this oncogenic pathway. In C. elegans, the sumoylation pathway and a combination of histone tail modifications regulate gene expression to attenuate the LET-60 (RAS) signalling pathway. We hypothesised that a number of chromatin regulators are likely to depend on sumoylation to attenuate the pathway. To reveal these, we designed an RNAi-based dimorphic genetic screen that selects candidates based on their ability to act as enhancers of a sumo mutant phenotype, such interactions would suggest that the candidates may be physically associated with sumoylation. We found 16 enhancers, one of which BET-1, is a conserved double bromodomain containing protein. We further characterised BET-1 and showed that it can physically associate with SMO-1 and UBC-9, and that it can be sumoylated in vitro within the second bromodomain at lysine 252. Previous work has shown that BET-1 can bind acetyl-lysines on histone tails to influence gene expression. In conclusion, our screening approach has identified BET-1 as a Sumo-dependent attenuator of LET-60-mediated signalling and our characterisation suggests that BET-1 can be sumoylated.
Highlights
It has been long established that the conserved RAS/RAF/ MAPK signalling pathway can act as an oncogenic pathway in different types of cancer [1,2,3,4]
We provide multiple lines of evidence that a sumoylated BET-1 influences attenuation of LET-60 signalling: loss of both BET-1 and SMO-1 together produces the same effect on LET-60 signalling as the loss of either of them; BET-1 physically interacts with SMO-1 and UBC-9; and BET-1 can be sumoylated in vitro
Since BET-1 is a reader of the epigenetic code, of acetyl-lysines on histone tails, it is interesting to speculate that sumoylation of BET-1 could regulate its ability to bind modified acetylated histone tails
Summary
It has been long established that the conserved RAS/RAF/ MAPK signalling pathway can act as an oncogenic pathway in different types of cancer [1,2,3,4]. In C. elegans, growth factors such as EGF or FGF mostly signal via activation of LET-60 (RAS) and recruitment of LIN-45 (RAF) to the plasma membrane [8]. This leads to a series of phosphorylation events that culminate in the transfer of MPK-1 (MAPK) to the nucleus. MAPK phosphorylates an array of nuclear targets, including transcription factors and components of chromatin modifying complexes [8] This impacts on gene expression and produces a negative feedback loop important to prevent hyperactivation of the RAS/RAF/ MAPK signalling cascade (Figure 1A) [5,6,7]
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