Telomere shortening can induce replica-tive senescence, which blocks cell division. Malignant cells bypass this arrest and become immortalized by activating two known telomere maintenance mechanisms: the reactivation of telomerase or the alternative lengthening of telomeres (ALT).1 Tumors using ALT for telomere maintenance will be refractory to treatment with telomerase inhibitors.2 Several unique features are found in human ALT-positive cells compared with telomerase-positive tumor cells. In addition to the lack of significant levels of telomerase activity, ALT-positive cells have telomeres that are highly heterogeneous in length, ranging from very long to very short.2'3 The other hallmark of ALT-positive cells is the presence of ALT-associated promy-elocytic leukemia (PML) bodies (APBs) containing (TTAGGG)n DNA, telom-ere-binding proteins and several proteins involved in DNA synthesis and recombination.4 Recent study showed that restoring p53 function in ALT cells caused p21 upregulation and a large increase of APBs. Knockdown of p21 significantly reduced p53-mediated induction of APBs.
展开▼
