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Significance Mammalian cells contain two RNA polymerase III isoforms that differ only in ubiquitous POLR3GL and developmentally regulated POLR3G subunits. Here, in contradiction to previous conclusions from POLR3G knockdown analyses, we show that POLR3G and POLR3GL are functionally redundant and, in the context of embryonic stem cell differentiation, can largely compensate for each other when expressed at appropriate levels. Moreover, whereasPolr3g knockout mice die at an early embryonic stage,Polr3gl knockout mice complete embryonic development but die at weaning with signs of both general growth defects and potential cerebellum-related neuronal defects. As interests grow in reported Pol III-related disorders,Polr3gl knockout mice provide a convenient model to study the physiological effect of variations in Pol III functions in more detail.

Functions of paralogous RNA polymerase III subunits POLR3G and POLR3GL in mouse development