The molecular chaperone Hsp90 regulates accumulation of DNA polymerase eta at replication stalling sites in UV-irradiated cells.
DNA polymerase eta (Pol eta) is a member of the mammalian Y family polymerases and performs error-free translesion synthesis across UV-damaged DNA. For this function, Pol eta 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 eta, which regulate its accumulation in replication foci. Here, we report that the molecular chaperone Hsp90 promotes UV irradiation-induced nuclear focus formation of Pol eta through control of its stability and binding to monoubiquitinated PCNA. Our data indicate that Hsp90 facilitates the folding of Pol eta 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 eta-dependent manner. Our studies identify Hsp90 as an essential regulator of Pol eta-mediated translesion synthesis.
Laboratory of Molecular Genetics, The Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
Takayuki
T
Sekimoto
Tsukasa
T
Oda
Franklin Mayca
FM
Pozo
Yoshiki
Y
Murakumo
Chikahide
C
Masutani
Fumio
F
Hanaoka
Takayuki
T
Yamashita
D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D004249:DNA Damage; D004261:DNA Replication / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000032:analysis / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
D016227:Benzoquinones; D004259:DNA-Directed DNA Polymerase; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018809:Proliferating Cell Nuclear Antigen; D046988:Proteasome Endopeptidase Complex; C112765:tanespimycin; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases