Gray Institute for Radiation Oncology and Biology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK.
Mol Cell. 2011 Mar 4;41(5):609-15. doi: 10.1016/j.molcel.2011.02.016.
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 β) and demonstrate that USP47 is required for stability of newly synthesized cytoplasmic Pol β that is used as a source for nuclear Pol β involved in DNA repair. We further show that knockdown of USP47 causes an increased level of ubiquitylated Pol β, decreased levels of Pol β, and a subsequent deficiency in BER, leading to accumulation of DNA strand breaks and decreased cell viability in response to DNA damage. Taken together, these data demonstrate an important role for USP47 in regulating DNA repair and maintaining genome integrity.
DNA 碱基切除修复 (BER) 是细胞维持基因组稳定性所必需的基本过程，BER 调控失常与过早衰老、突变率增加以及癌症发生密切相关。我们现已鉴定出胞质泛素特异性蛋白酶 USP47 是关键 BER DNA 聚合酶（Pol β）去泛素化的主要酶，并证实 USP47 对于新合成的细胞质 Pol β 的稳定性是必需的，细胞质 Pol β 作为参与 DNA 修复的核 Pol β 的来源。我们进一步发现，USP47 的敲低会导致泛素化 Pol β 的水平增加、Pol β 水平降低以及随后的 BER 缺陷，导致 DNA 链断裂的积累和对 DNA 损伤的细胞活力降低。总之，这些数据表明 USP47 在调节 DNA 修复和维持基因组完整性方面发挥着重要作用。
