Replication protein A prevents accumulation of single-stranded telomeric DNA in cells that use alternative lengthening of telomeres |
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Authors: | Grudic Amra Jul-Larsen Asne Haring Stuart J Wold Marc S Lønning Per Eystein Bjerkvig Rolf Bøe Stig Ove |
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Affiliation: | Amra Grudic, Åsne Jul-Larsen, Stuart J. Haring, Marc S. Wold, Per Eystein Lønning, Rolf Bjerkvig, and Stig Ove Bøe |
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Abstract: | The activation of a telomere maintenance mechanism is required for cancer development in humans. While most tumors achieve this by expressing the enzyme telomerase, a fraction (5–15%) employs a recombination-based mechanism termed alternative lengthening of telomeres (ALT). Here we show that loss of the single-stranded DNA-binding protein replication protein A (RPA) in human ALT cells, but not in telomerase-positive cells, causes increased exposure of single-stranded G-rich telomeric DNA, cell cycle arrest in G2/M phase, accumulation of single-stranded telomeric DNA within ALT-associated PML bodies (APBs), and formation of telomeric aggregates at the ends of metaphase chromosomes. This study demonstrates differences between ALT cells and telomerase-positive cells in the requirement for RPA in telomere processing and implicates the ALT mechanism in tumor cells as a possible therapeutic target. |
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