Sex-lethal imparts a sex-specific function to UNR by recruiting it to the msl-2 mRNA 3′ UTR: translational repression for dosage compensation

Abstract

MSL-2 (male-specific lethal 2) is the limiting component of the Drosophila dosage compensation complex (DCC) that specifically increases transcription from the male X chromosome. Ectopic expression of MSL-2 protein in females causes DCC assembly on both X chromosomes and lethality. Inhibition of MSL-2 synthesis requires the female-specific protein sex-lethal (SXL), which binds to the msl-2 mRNA 5 and 3 untranslated regions (UTRs) and blocks translation through distinct UTR-specific mechanisms. Here, we purify translationally silenced msl-2 mRNPs and identify UNR (upstream of N-ras) as a protein recruited to the 3 UTR by SXL. We demonstrate that SXL requires UNR as a corepressor for 3-UTR-mediated regulation, imparting a female-specific function to the ubiquitously expressed UNR protein. Our results reveal a novel functional role for UNR as a translational repressor and indicate that UNR is a key component of a "fail-safe" dosage compensation regulatory system that prevents toxic MSL-2 synthesis in female cells.[Keywords: Translational control; dosage compensation; mRNP; cold shock domain; female cell line; sex-specific function] Supplemental material is available at http://www.genesdev.org.

Unr, a cytoplasmic RNA-binding protein with cold-shock domains, is involved in control of apoptosis in ES and HuH7 cells

“…Second, Unr has been characterized as a translational regulator. Unr is required for translational repression of male-specific lethal 2 mRNA, for X-chromosome dosage compensation Duncan et al, 2006). Unr is also a factor required for internal initiation of translation (Hunt et al, 1999), a process that allows cap-independent recruitment of ribosomes to mRNA.…”

UNR facilitates the interaction of MLE with the lncRNA roX2 during Drosophila dosage compensation

“…Our current data now suggest that the general RBP UNR facilitates this interaction. Remarkably, UNR also binds and regulates the activity of msl2 mRNA together with the sex determination switch SXL 9,18 , suggesting that sex determination and dosage compensation have co-evolved to employ similar factors from the large portfolio of RBPs. UNR, thus, extends the small list of RBPs involved in dosage compensation.…”

Widespread generation of alternative UTRs contributes to sex-specific RNA binding by UNR

“…3). Precedence for sex-specific binding existed from the known UNR targets msl2 and roX Duncan et al 2006;Patalano et al 2009). In the case of msl2, UNR is recruited to the 39 UTR of the transcript by the sex-specific protein SXL .…”

“…X-chromosome dosage compensation is the process that equalizes the expression of X-linked genes between males (XY) and females (XX), and in Drosophila is achieved by hypertranscription of the single male X chromosome by the dosage compensation complex (DCC), a ribonucleoprotein assembly of at least five proteins (MSL1, MSL2, MSL3, MOF, and MLE) and two noncoding RNAs (roX1 and roX2) (Gelbart and Kuroda 2009). In females, UNR binds to msl2 mRNA and inhibits its translation, contributing to repressing dosage compensation Duncan et al 2006;Patalano et al 2009). Binding of UNR to msl2 mRNA depends on the female-specific RBP Sex-lethal (SXL), which, in addition to recruiting UNR to the 39 UTR of msl2, promotes the retention of a facultative intron in msl2 59 UTR (for review, see Graindorge et al 2011).…”