精氨酸甲基化调节DNA聚合酶β。

Arginine methylation regulates DNA polymerase beta.

作者信息

El-Andaloussi Nazim, Valovka Taras, Toueille Magali, Steinacher Roland, Focke Frauke, Gehrig Peter, Covic Marcela, Hassa Paul O, Schär Primo, Hübscher Ulrich, Hottiger Michael O

机构信息

Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

出版信息

Mol Cell. 2006 Apr 7;22(1):51-62. doi: 10.1016/j.molcel.2006.02.013.

DOI:10.1016/j.molcel.2006.02.013

PMID:16600869

Abstract

Alterations in DNA repair lead to genomic instability and higher risk of cancer. DNA base excision repair (BER) corrects damaged bases, apurinic sites, and single-strand DNA breaks. Here, a regulatory mechanism for DNA polymerase beta (Pol beta) is described. Pol beta was found to form a complex with the protein arginine methyltransferase 6 (PRMT6) and was specifically methylated in vitro and in vivo. Methylation of Pol beta by PRMT6 strongly stimulated DNA polymerase activity by enhancing DNA binding and processivity, while single nucleotide insertion and dRP-lyase activity were not affected. Two residues, R83 and R152, were identified in Pol beta as the sites of methylation by PRMT6. Genetic complementation of Pol beta knockout cells with R83/152K mutant revealed the importance of these residues for the cellular resistance to DNA alkylating agent. Based on our findings, we propose that PRMT6 plays a role as a regulator of BER.

摘要

DNA修复的改变会导致基因组不稳定和患癌风险增加。DNA碱基切除修复（BER）可纠正受损碱基、脱嘌呤位点和单链DNA断裂。本文描述了一种针对DNA聚合酶β（Polβ）的调控机制。研究发现，Polβ与蛋白质精氨酸甲基转移酶6（PRMT6）形成复合物，并在体外和体内发生特异性甲基化。PRMT6介导的Polβ甲基化通过增强DNA结合能力和持续合成能力，强烈刺激了DNA聚合酶活性，而单核苷酸插入和dRP裂解酶活性则不受影响。在Polβ中鉴定出两个残基R83和R152为PRMT6的甲基化位点。用R83/152K突变体对Polβ基因敲除细胞进行基因互补，揭示了这些残基对细胞抵抗DNA烷化剂的重要性。基于我们的研究结果，我们提出PRMT6作为BER的调节剂发挥作用。