The RNA transport factor PHAX is required for proper histone H2AX expression and DNA damage response.

PHAX (phosphorylated adaptor for RNA export) promotes nuclear export of short transcripts of RNA polymerase II such as spliceosomal U snRNA precursors, as well as intranuclear transport of small nucleolar RNAs (snoRNAs). However, it remains unknown whether PHAX has other critical functions. Here we show that PHAX is required for efficient DNA damage response (DDR) via regulation of phosphorylated histone variant H2AX (γH2AX), a key factor for DDR. Knockdown of PHAX led to a significant reduction of H2AX mRNA levels, through inhibition of both transcription of the H2AX gene and nuclear export of H2AX mRNA, one of the shortest mRNAs in the cell. As a result, PHAX-knockdown cells become more sensitive to DNA damage due to a shortage of γH2AX. These results reveal a novel function of PHAX, which secures efficient DDR and hence genome stability. © 2020 Machitani et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

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