FEN1 contributes to telomere stability in ALT-positive tumor cells.
Abrogation of telomere stability through loss-of-function mutations in telomere binding proteins contributes to genomic instability and cancer progression. Recently, Flap endonuclease 1 (FEN1) was shown to contribute to telomere stability in human cells that had not yet activated a telomere maintenance mechanism, suggesting that abrogation of FEN1 function influences the transformation process by compromising telomere stability and driving genomic instability. Here, we analyse the telomeres in human cancer cells following FEN1 depletion. We show that FEN1 is required for telomere stability in cells that rely on the alternative lengthening of telomere (ALT) mechanism. Indeed, FEN1 depletion resulted in telomere dysfunction, characterized by formation of telomere dysfunction-induced foci (TIFs) and end-to-end fusions in ALT-positive cells. In contrast, no telomere phenotype was observed in telomerase-positive cells on FEN1 depletion, suggesting that ongoing telomerase activity protected telomeres. In consonance with this, we found that expression of the catalytic component of telomerase (hTERT) but not an inactive allele rescued telomere dysfunction on FEN1 depletion in ALT cells. Our data suggest that mutations that arise in FEN1 affect telomere stability and genome fidelity by promoting telomere fusions and anaphase-bridge-breakage cycles, which further drive genome instability and thereby contribute to the transformation process.
Saharia
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Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Stewart
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SA
D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045585:Flap Endonucleases / Q000502:physiology*; D042822:Genomic Instability; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D034741:RNA, Small Interfering; C509186:TERT protein, human; D019098:Telomerase; D045585:Flap Endonucleases; C468317:FEN1 protein, human