Orren D K, Machwe A, Karmakar P, Piotrowski J, Cooper M P, Bohr V A
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Nucleic Acids Res. 2001 May 1;29(9):1926-34. doi: 10.1093/nar/29.9.1926.
Werner syndrome (WS) is a premature aging disorder where the affected individuals appear much older than their chronological age. The single gene that is defective in WS encodes a protein (WRN) that has ATPase, helicase and 3'-->5' exonuclease activities. Our laboratory has recently uncovered a physical and functional interaction between WRN and the Ku heterodimer complex that functions in double-strand break repair and V(D)J recombination. Importantly, Ku specifically stimulates the exonuclease activity of WRN. We now report that Ku enables the Werner exonuclease to digest through regions of DNA containing 8-oxoadenine and 8-oxoguanine modifications, lesions that have previously been shown to block the exonuclease activity of WRN alone. These results indicate that Ku significantly alters the exonuclease function of WRN and suggest that the two proteins function concomitantly in a DNA damage processing pathway. In support of this notion we also observed co-localization of WRN and Ku, particularly after DNA damaging treatments.
沃纳综合征（WS）是一种早衰性疾病，患病个体看起来比其实际年龄老得多。导致WS的单基因编码一种具有ATP酶、解旋酶和3'→5'核酸外切酶活性的蛋白质（WRN）。我们实验室最近发现WRN与Ku异源二聚体复合物之间存在物理和功能上的相互作用，Ku异源二聚体复合物在双链断裂修复和V（D）J重组中发挥作用。重要的是，Ku能特异性刺激WRN的核酸外切酶活性。我们现在报告，Ku能使沃纳核酸外切酶消化含有8-氧代腺嘌呤和8-氧代鸟嘌呤修饰的DNA区域，这些损伤先前已被证明会单独阻断WRN的核酸外切酶活性。这些结果表明，Ku显著改变了WRN的核酸外切酶功能，并表明这两种蛋白质在DNA损伤处理途径中协同发挥作用。支持这一观点的是，我们还观察到WRN和Ku的共定位，尤其是在DNA损伤处理后。
