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GeezerVison is showing en.wikipedia.org — Sex-lethal - Wikipedia
 Sex-lethal (Sxl) is the master regulatory gene for both sex determination and dosage compensation in Drosophila melanogaster (P19339), where it functions as an RNA-binding protein.[1][2][3] Named for its mutation phenotype in D. melanogaster, Sxl is found in Dipteran insects. Though present in both sexes, Sxl's activity is female-specific in D. melanogaster.[3] It is most closely related to the ELAV/HUD subfamily of splicing factors.[4] Mechanism of ActionIn D. melanogaster, Sxl exerts its effects primarily through post-transcriptional regulation, specifically alternative splicing and translational repression.[3] It regulates at least three key target genes: *Sxl* itself (autoregulation), *transformer (tra)* (sex determination), and *male-specific lethal-2 (msl-2)* (dosage compensation).[3] AutoregulationSxl regulates its own expression through a positive feedback loop in females. This involves alternative splicing of the *Sxl* pre-mRNA. In males, the *Sxl* transcript includes a "male-specific exon" (exon 3) that contains an early stop codon, resulting in a truncated, non-functional protein. In females, Sxl protein binds to its own pre-mRNA at multiple sites, both upstream and downstream of the male-specific exon. This binding primarily influences the selection of the 5' splice site of the male exon, promoting the skipping of the male-specific exon and the production of a full-length, functional Sxl protein.[5][6] The protein PPS interacts with Sxl and helps mediate this effect.[7] *transformer* RegulationIn fruit flies, Sxl protein participates in alternative splicing of the transformer gene, ultimately deciding the sex of the fly.[8] Sxl induces female-specific alternative splicing of the transformer (tra) pre-mRNA by binding to uridine-rich polypyrimidine tracts near the non-sex-specific 3' splice site. This binding prevents the general splicing factor U2AF from binding, thus promoting the use of a female-specific upstream 3' splice site. *msl-2* RegulationSxl regulates *male-specific lethal-2 (msl-2)*, a key component of the dosage compensation complex, through a combination of alternative splicing and translational repression.[9][10] Sxl binds to both the 5' and 3' UTRs of *msl-2* mRNA. The binding in the 5' UTR leads to the retention of an intron containing a stop codon, while binding in both UTRs contributes to translational repression. This prevents the production of MSL-2 protein in females, thereby preventing dosage compensation from occurring. Additional Targets and Translational ControlBeyond *tra* and *msl-2*, Sxl has been shown to affect the expression of other genes. RIP-seq analysis has identified hundreds of potential Sxl targets in primordial germ cells, suggesting a broader role in gene regulation. Sxl also regulates gene expression by repressing translation, binding to both the 5' and 3'UTRs. Protein StructureSXL contains an N-terminal Gly/Asn-rich domain that may be responsible for protein-protein interaction, and tandem RNA recognition motifs (RRMs) that show high preference for binding single-stranded, uridine-rich target RNA transcripts.[11] The crystal structure of the tandem RRMs bound to a *tra*-derived RNA reveals a V-shaped cleft where the RNA binds. Notably, there are no interdomain contacts between the RRMs in the absence of RNA, indicating conformational flexibility.[12] Evolution
Protein InteractionsSxl is known to interact with several other proteins, including:
Mutations and PhenotypesThe name "Sex-lethal" derives from the fact that loss-of-function mutations are lethal in females (XX individuals) due to misregulation of dosage compensation. Some *Sxl* alleles cause female sterility rather than lethality. Conversely, gain-of-function *Sxl* alleles can be lethal in males. Mutations in *Sxl* can also affect sexual behavior and pheromone production. Somatic mosaic females that carry mutations in the *Sxl* gene develop abnormal genitalia and reproductive tissue. References
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