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A Novel Telomere Structure in a Human Alternative Lengthening of Telomeres Cell Line

¹ Department of Medicine, University of Texas Health Science Center at San Antonio, ² South Texas Veterans Health Care System, San Antonio, Texas; ³ Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; and ⁴ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: F. Brad Johnson, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 405A Stellar Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104-6100. Phone: 215-573-5037; Fax: 215-573-6317; E-mail: johnsonb{at}mail.med.upenn.edu. or Robert A. Marciniak, Department of Medicine, University of Texas Health Science Center at San Antonio, 7730 Floyd Curl Drive, MSC 7884, San Antonio, TX 78229-3900. Phone: 210-567-4777; Fax: 617-507-3491; E-mail: marciniak{at}uthscsa.edu.

Cancer cells require mechanisms to maintain telomeres. Most use telomerase, but 5% to 20% of tumors use alternative lengthening of telomeres (ALT), a telomerase-independent mechanism that seems to depend on recombination. ALT is characterized by amplification of telomere TTAGGG repeats to lengths beyond 50 kb, by elevated rates of telomere recombination, and by nuclear structures called ALT-associated promyelocytic leukemia bodies. In Saccharomyces cerevisiae, survivors of telomerase inactivation also use recombination to maintain telomeres. There are two types of survivors, which differ in telomere structure. The first possesses telomere repeats and the Y' subtelomeric element amplified together as a tandem array at chromosome termini (type I), and the other possesses amplification of telomeric repeats alone (type II), similar to previously described human ALT cells. Here, we describe the first human ALT cell line having "tandem array" telomeres with a structure similar to that of type I yeast survivors. The chromosome termini consist of a repeat unit containing 2.5 kb of SV40 DNA and a variable amount of TTAGGG sequence repeated in tandem an average of 10 to 20 times. Similar to previously described ALT cells, they show evidence of telomere recombination, but unlike standard ALT cells, they lack ALT-associated promyelocytic leukemia bodies and their telomeres are transcribed. These findings have implications for the pathogenesis and diagnosis of cancer.

Key Words: telomeres • recombination • ALT • Werner syndrome • SV40

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