Introduction

Sex lethal (Sxl) is an RNA-binding protein that plays a vital role in sex determination and dosage compensation in Drosophila melanogaster, the common fruit fly ^[1]. Sxl binds specifically to the continuous single-stranded RNA sequence 5’-UGUUUUUUU ^[2]. Functional copies of Sxl are expressed only in female fruit flies, where they induce sex-specific splicing patterns in the transcript of the Transformer (Tra) gene that lead to its function. Tra initiates a cascade that results in the development of female structures and behaviors. Sxl binds to its recognition element in the Tra pre-mRNA transcript, thereby blocking association of the splicing factor U2AF at the nearby splice site. Without the association of this essential splicing factor, the 3’ splice site shifts downstream, causing the removal of a premature stop codon and preventing truncation and inactivation of the Tra protein ^[1]. The pre-mRNA transcript of Male-specific lethal 2 (Msl2) is the downstream target through which Sxl regulates dosage compensation. Active Sxl protein (in females) binds to two recognition elements on Msl2 causing the retention of the first intron in the 5’UTR of Msl2. Sxl bound at this intron then blocks translation, preventing expression of Msl2 in females ^[1]. Without Msl2 protein, the Male specific lethal complex cannot form and carry out its function of upregulating expression of genes on the X chromosome ^[3].

Structure

Mutation