USP47 Is a Deubiquitylating Enzyme that Regulates Base Excision Repair by Controlling Steady-State Levels of DNA Polymerase β

DNA base excision repair (BER) is an essential cellular process required for genome stability, and misregulation of BER is linked to premature aging, increased rate of mutagenesis, and cancer. We have now identified the cytoplasmic ubiquitin-specific protease USP47 as the major enzyme involved in deubiquitylation of the key BER DNA polymerase (Pol beta) and demonstrate that USP47 is required for stability of newly synthesized cytoplasmic Pol beta that is used as a source for nuclear Pol beta involved in DNA repair. We further show that knockdown of USP47 causes an increased level of ubiquitylated Pol beta, decreased levels of Pol beta, and a subsequent deficiency in BER, leading to accumulation of DNA strand breaks and decreased cell viability M response to DNA damage. Taken together, these data demonstrate an important role for USP47 in regulating DNA repair and maintaining genome integrity.