title: SMARCAL1 Resolves Replication Stress at ALT Telomeres.
abstract: Cancer cells overcome replicative senescence by exploiting mechanisms of telomere elongation, a process often accomplished by reactivation of the enzyme telomerase. However, a subset of cancer cells lack telomerase activity and rely on the alternative lengthening of telomeres (ALT) pathway, a recombination-based mechanism of telomere elongation. Although the mechanisms regulating ALT are not fully defined, chronic replication stress at telomeres might prime these fragile regions for recombination. Here, we demonstrate that the replication stress response protein SMARCAL1 is a critical regulator of ALT activity. SMARCAL1 associates with ALT telomeres to resolve replication stress and ensure telomere stability. In the absence of SMARCAL1, persistently stalled replication forks at ALT telomeres deteriorate into DNA double-strand breaks promoting the formation of chromosome fusions. Our studies not only define a role for SMARCAL1 in ALT telomere maintenance, but also demonstrate that resolution of replication stress is a crucial step in the ALT mechanism.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Medicine, Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Kelli E
authors.initials: KE
authors.lastname: Cox
authors.affiliation: Department of Biology, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Maréchal
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Medicine, Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: rlflynn@bu.edu.
authors.forename: Rachel Litman
authors.initials: RL
authors.lastname: Flynn
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000378:metabolism*; D006801:Humans; D051135:Rad51 Recombinase / Q000378:metabolism; D013312:Stress, Physiological; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis
chemical_list: D051135:Rad51 Recombinase; C412482:SMARCAL1 protein, human; D004265:DNA Helicases
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