Laud Purnima R, Multani Asha S, Bailey Susan M, Wu Ling, Ma Jin, Kingsley Charles, Lebel Michel, Pathak Sen, DePinho Ronald A, Chang Sandy
Department of Molecular Genetics, University of Texas, The M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Genes Dev. 2005 Nov 1;19(21):2560-70. doi: 10.1101/gad.1321305.
Werner Syndrome (WS) is characterized by premature aging, genomic instability, and cancer. The combined impact of WRN helicase deficiency and limiting telomere reserves is central to disease pathogenesis. Here, we report that cells doubly deficient for telomerase and WRN helicase show chromosomal aberrations and elevated recombination rates between telomeres of sister chromatids. Somatic reconstitution of WRN function, but not a WRN helicase-deficient mutant, abolished telomere sister chromatid exchange (T-SCE), indicating that WRN normally represses T-SCEs. Elevated T-SCE was associated with greater immortalization potential and resultant tumors maintained telomeres via the alternative lengthening of telomere (ALT) pathway. We propose that the increased incidence of chromosomal instability and cancer in WS relates in part to aberrant recombinations between sister chromatids at telomeres, which facilitates the activation of ALT and engenders cancer-relevant chromosomal aberrations and tumor formation.
沃纳综合征（WS）的特征是早衰、基因组不稳定和癌症。WRN解旋酶缺乏和有限的端粒储备的综合影响是疾病发病机制的核心。在此，我们报告，端粒酶和WRN解旋酶双缺陷的细胞表现出染色体畸变以及姐妹染色单体端粒之间的重组率升高。WRN功能的体细胞重建，而非WRN解旋酶缺陷突变体，消除了端粒姐妹染色单体交换（T-SCE），表明WRN通常抑制T-SCE。T-SCE升高与更高的永生化潜能相关，并且由此产生的肿瘤通过端粒替代延长（ALT）途径维持端粒。我们提出，WS中染色体不稳定和癌症发生率增加部分与端粒处姐妹染色单体之间的异常重组有关，这促进了ALT的激活并导致与癌症相关的染色体畸变和肿瘤形成。
