Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California 94143, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA.
RNA. 2021 Dec;27(12):1577-1588. doi: 10.1261/rna.078926.121. Epub 2021 Sep 17.
DDX3 is a DEAD-box RNA helicase that regulates translation and is encoded by the X- and Y-linked paralogs and 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 mediate a class of developmental disorders called DDX3X syndrome, while loss of is implicated in male infertility. One possible explanation for female-bias in DDX3X syndrome is that 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 the context of mRNA translation 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.
DDX3 是一种 DEAD 框 RNA 解旋酶，可调节翻译，由 X 和 Y 连锁的同源物 和 编码。虽然 DDX3X 在人类组织中广泛表达，对生存至关重要，但 DDX3Y 是男性特异性的，在体细胞组织中的表达水平低于 DDX3X，且变异性更大。 中的杂合遗传病变介导了一类称为 DDX3X 综合征的发育障碍，而 的缺失与男性不育有关。DDX3X 综合征女性偏倚的一个可能解释是 编码具有不同生化活性的多肽。在这项研究中，我们使用核糖体谱和体外翻译来证明 DDX3 的 X 和 Y 连锁同源物在翻译中发挥功能冗余作用。我们发现，受 DDX3X 耗竭或突变影响的转录本可以通过与 DDX3Y 互补来挽救。我们的数据表明，在人类细胞中，mRNA 翻译的背景下，DDX3X 和 DDX3Y 蛋白可以相互功能互补。DDX3Y 不在大部分中枢神经系统中表达。这些发现表明，表达差异而非依赖于同源物的蛋白合成差异，是 DDX3X 相关疾病性别偏倚的基础。
