The Molecular Chaperone Hsp90 Regulates Accumulation of DNA Polymerase η at Replication Stalling Sites in UV-Irradiated Cells

SummaryDNA polymerase η (Pol η) is a member of the mammalian Y family polymerases and performs error-free translesion synthesis across UV-damaged DNA. For this function, Pol η accumulates in nuclear foci at replication stalling sites via its interaction with monoubiquitinated PCNA. However, little is known about the posttranslational control mechanisms of Pol η, which regulate its accumulation in replication foci. Here, we report that the molecular chaperone Hsp90 promotes UV irradiation-induced nuclear focus formation of Pol η through control of its stability and binding to monoubiquitinated PCNA. Our data indicate that Hsp90 facilitates the folding of Pol η into an active form in which PCNA- and ubiquitin-binding regions are functional. Furthermore, Hsp90 inhibition potentiates UV-induced cytotoxicity and mutagenesis in a Pol η-dependent manner. Our studies identify Hsp90 as an essential regulator of Pol η-mediated translesion synthesis.

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