Females have an extra X chromosome as compared to males, and this can mean trouble – think of what happens when someone has an extra copy of any other chromosome, 21 being the most (in)famous! Dosage compensation is therefore essential, and there’s different ways of dealing with it. In humans, women inactivate one of their X chromosomes, while in the fruifly the opposite happens: males overactivate their only copy of X.
The complex in charge of doing so is called MSL and male-specific-lethal-2 (msl2) is one of its subunits. Female flies must inhibit this gene in order to survive, and Sex-lethal (SXL) is the protein which orchestrates this repression. So far, it was known that SXL binds to the 5′ and 3′ untranslated regions (UTRs) of the msl2 mRNA, inhibiting splicing in the nucleus and subsequent translation in the cytoplasm.
But Fatima Gebauer and colleagues at the CRG have now found a third way SXL can repress msl2: by inhibition of nucleocytoplasmic transport of msl2 mRNA.
To identify SXL cofactors in msl2 regulation, the researchers from the Regulation of Protein Synthesis in Eukaryotes group devised a two-step purification method termed GRAB (GST pull-down and RNA affinity binding) and identified Held-Out-Wings (HOW) as a component of the msl2 5′ UTR-associated complex.
Their experiments showed that HOW directly interacts with SXL and binds to two sequence elements in the msl2 5′ UTR. Depletion of HOW reduced the capacity of SXL to repress the expression of msl2 reporters without affecting SXL-mediated regulation of splicing or translation. Instead, HOW was required for SXL to retain msl2 transcripts in the nucleus.
These results, published in Genes & Development uncover a novel function of SXL in (msl2) nuclear mRNA retention – a third way for female control of sex-specific gene expression.
Graindorge A, Carré C, Gebauer F. Sex-lethal promotes nuclear retention of msl2 mRNA via interactions with the STAR protein HOW. Genes Dev. 2013 Jun 15;27(12):1421-33