DDX3X and DDX3Y are redundant in protein synthesis

Abstract

DDX3 is a DEAD-box RNA helicase that regulates translation and is encoded by the X- and Y-linked paralogs DDX3X and DDX3Y. While DDX3X is ubiquitously expressed in human tissues and essential for viability, DDX3Y is male-specific and shows lower and more variable expression than DDX3X in somatic tissues. Heterozygous genetic lesions in DDX3X mediate a class of developmental disorders called DDX3X syndrome, while loss of DDX3Y is implicated in male infertility. One possible explanation for female-bias in DDX3X syndrome is that DDX3Y encodes a polypeptide with different biochemical activity. In this study, we use ribosome profiling and in vitro translation to demonstrate that the X- and Y-linked paralogs of DDX3 play functionally redundant roles in translation. We find that transcripts that are sensitive to DDX3X depletion or mutation are rescued by complementation with DDX3Y. Our data indicate that DDX3X and DDX3Y proteins can functionally complement each other in human cells. DDX3Y is not expressed in a large fraction of the central nervous system. These findings suggest that expression differences, not differences in paralog-dependent protein synthesis, underlie the sex-bias of DDX3X-associated diseases.

Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis

“…While we do not exclude subtle differences in the target repertoire, our data, combined with the almost complete amino acid conservation in the helicase RNA-interacting domain, support a model in which the ectopic expression of DDX3Y acts to rescue the translational defect associated with the loss of DDX3X. Recently published data support a redundancy between DDX3X and DDX3Y (Venkataramanan et al, 2020). This potential to reactivate DDX3Y may contribute to the sex bias seen in BL and other male-skewed cancers in which DDX3X is target.…”

Gene essentiality in cancer cell lines is modified by the sex chromosomes

“…This might also explain the excess somatic mutations in X-linked genes with a Y paralog in male tumors. Among the four genes we found to be explained by Y-specific redundancy (DDX3X, EIF1AX, RPS4X, and ZFX), two (DDX3X and RPS4X) were previously reported to have redundant roles with their Y paralogs based on functional experiments (Venkataramanan et al, 2020;Watanabe et al, 1993). For all four genes, the average dependency score in Y + cells was still substantially lower than 0, indicating that the loss of those X-linked genes causes decreased cell viability even with compensation by Y-linked genes.…”

Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

“…Although we have not observed LOY across the GTEx dataset, it is possible that alternative mechanisms may also lead to down-regulation of the chrY expressed paralog in normal tissues. While not explicitly addressed, recent studies imply incomplete redundancy for EIF1AX-EIF1AY and DDX3X-DDX3Y in different contexts in absence of LOY [68][69][70] .…”