title: The roles of WRN and BLM RecQ helicases in the Alternative Lengthening of Telomeres.
abstract: Approximately 10% of all cancers, but a higher proportion of sarcomas, use the recombination-based alternative lengthening of telomeres (ALT) to maintain telomeres. Two RecQ helicase genes, BLM and WRN, play important roles in homologous recombination repair and they have been implicated in telomeric recombination activity, but their precise roles in ALT are unclear. Using analysis of sequence variation present in human telomeres, we found that a WRN- ALT+ cell line lacks the class of complex telomere mutations attributed to inter-telomeric recombination in other ALT+ cell lines. This suggests that WRN facilitates inter-telomeric recombination when there are sequence differences between the donor and recipient molecules or that sister-telomere interactions are suppressed in the presence of WRN and this promotes inter-telomeric recombination. Depleting BLM in the WRN- ALT+ cell line increased the mutation frequency at telomeres and at the MS32 minisatellite, which is a marker of ALT. The absence of complex telomere mutations persisted in BLM-depleted clones, and there was a clear increase in sequence homogenization across the telomere and MS32 repeat arrays. These data indicate that BLM suppresses unequal sister chromatid interactions that result in excessive homogenization at MS32 and at telomeres in ALT+ cells.
authors.affiliation: Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK.
authors.forename: Aaron
authors.initials: A
authors.lastname: Mendez-Bermudez
authors.forename: Alberto
authors.initials: A
authors.lastname: Hidalgo-Bravo
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Cotton
authors.forename: Athanasia
authors.initials: A
authors.lastname: Gravani
authors.forename: Jennie N
authors.initials: JN
authors.lastname: Jeyapalan
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Royle
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D015536:Down-Regulation; D005090:Exodeoxyribonucleases / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D053484:RecQ Helicases / Q000378:metabolism / Q000502:physiology*; D016615:Telomere / Q000737:chemistry; D059505:Telomere Homeostasis; D000071657:Werner Syndrome Helicase
chemical_list: D005090:Exodeoxyribonucleases; C097151:Bloom syndrome protein; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase