The CHARGE syndrome-associated protein FAM172A controls AGO2 nuclear import

CHARGE syndrome is a neural crest-related disorder mainly caused by mutation of the chromatin remodeler-coding gene CHD7. Alter-native causes include mutation of other chromatin and/or splicing factors. One of these additional players is the poorly characterized FAM172A, which we previously found in a complex with CHD7 and the small RNA-binding protein AGO2 at the chromatin-spliceosome interface. Focusing on the FAM172A-AGO2 interplay, we now report that FAM172A is a direct binding partner of AGO2 and, as such, one of the long sought-after regulators of AGO2 nuclear import. We show that this FAM172A function mainly relies on its classical bipartite nuclear localization signal and associated canonical importin-alpha/beta pathway, being enhanced by CK2-induced phosphorylation and ab-rogated by a CHARGE syndrome-associated missense mutation. Overall, this study thus strengthens the notion that noncanonical nuclear functions of AGO2 and associated regulatory mechanisms might be clinically relevant.

Automated summary

CHARGE syndrome is primarily caused by CHD7 mutation, a chromatin remodeler-coding gene. FAM172A, a poorly characterized factor, is found to be a binding partner of AGO2 and regulates AGO2 nuclear import. The study highlights the importance of noncanonical nuclear functions of AGO2 and its regulatory mechanisms.