Machwe Amrita, Xiao Liren, Orren David K
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0305, USA.
Oncogene. 2004 Jan 8;23(1):149-56. doi: 10.1038/sj.onc.1206906.
The cancer-prone and premature aging disease Werner syndrome is due to loss of WRN gene function. Cells lacking WRN demonstrate genomic instability, including telomeric abnormalities and undergo premature senescence, suggesting defects in telomere metabolism. This notion is strongly supported by our finding of physical and functional interactions between WRN and TRF2, a telomeric repeat binding factor essential for proper telomeric structure. TRF2 binds to DNA substrates containing telomeric repeats and facilitates their degradation specifically by WRN exonuclease activity. WRN and TRF2 also interact directly in the absence of DNA. These results suggest that TRF2 recruits WRN for accurate processing of telomeric structures in vivo. Thus, our findings link problems in telomere maintenance to both carcinogenesis and specific features of aging.
易患癌症和早衰的沃纳综合征是由于WRN基因功能丧失所致。缺乏WRN的细胞表现出基因组不稳定，包括端粒异常，并会过早衰老，这表明端粒代谢存在缺陷。我们发现WRN与TRF2之间存在物理和功能相互作用，这一发现有力地支持了这一观点。TRF2是一种对维持正常端粒结构至关重要的端粒重复序列结合因子。TRF2与含有端粒重复序列的DNA底物结合，并通过WRN核酸外切酶活性促进其特异性降解。在没有DNA的情况下，WRN和TRF2也会直接相互作用。这些结果表明，TRF2招募WRN以在体内精确处理端粒结构。因此，我们的研究结果将端粒维持问题与致癌作用和衰老的特定特征联系起来。
