Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Cancer Res. 2013 Jul 15;73(14):4247-55. doi: 10.1158/0008-5472.CAN-12-3117. Epub 2013 May 16.
Germline mutations of the retinoblastoma gene (RB1) predispose to both sporadic and radiation-induced osteosarcoma, tumors characterized by high levels of genomic instability, and activation of alternative lengthening of telomeres. Mice with haploinsufficiency of the Rb1 gene in the osteoblastic lineage reiterate the radiation susceptibility to osteosarcoma seen in patients with germline RB1 mutations. We show that the susceptibility is accompanied by an increase in genomic instability, resulting from Rb1-dependent telomere erosion. Radiation exposure did not accelerate the rate of telomere loss but amplified the genomic instability resulting from the dysfunctional telomeres. These findings suggest that telomere maintenance is a noncanonical caretaker function of the retinoblastoma protein, such that its deficiency in cancer may potentiate DNA damage-induced carcinogenesis by promoting formation of chromosomal aberrations, rather than simply by affecting cell-cycle control.
种系突变的视网膜母细胞瘤基因（RB1）易患散发性和辐射诱导的骨肉瘤，肿瘤的特点是高水平的基因组不稳定性，并激活端粒的非经典延长。在成骨细胞系中 Rb1 基因的杂合不足的小鼠重复出现了在种系 RB1 突变的患者中观察到的对骨肉瘤的辐射易感性。我们表明，这种易感性伴随着基因组不稳定性的增加，这是由 Rb1 依赖性端粒侵蚀引起的。辐射暴露并没有加速端粒丢失的速度，而是放大了由功能失调的端粒引起的基因组不稳定性。这些发现表明，端粒维持是视网膜母细胞瘤蛋白的一种非经典的监管功能，因此其在癌症中的缺乏可能通过促进染色体畸变的形成，而不是简单地通过影响细胞周期控制，从而增强 DNA 损伤诱导的致癌作用。
