title: Infection with retroviral vectors leads to perturbed DNA replication increasing vector integrations into fragile sites.
abstract: Genome instability is a hallmark of cancer. Common fragile sites (CFSs) are specific regions in the human genome that are sensitive to replication stress and are prone to genomic instability in different cancer types. Here we molecularly cloned a new CFS, FRA11H, in 11q13. The genomic region of FRA11H harbors a hotspot of chromosomal breakpoints found in different types of cancer, indicating that this region is unstable during cancer development. We further found that FRA11H is a hotspot for integrations of Murine Leukemia Virus (MLV)-based vectors, following CD34+ infections in vitro as well as ex-vivo during gene therapy trials. Importantly, we found that the MLV-based vector infection in-vitro leads to replication perturbation, DNA damage and increased CFS expression. This suggests that infection by MLV-based vectors leads to replication-induced genome instability, raising further concerns regarding the use of retroviral vectors in gene therapy trials.
authors.affiliation: Department of Genetics, The Life Sciences Institute, Edmond J. Safra Campus, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Assaf C
authors.initials: AC
authors.lastname: Bester
authors.forename: Moshe
authors.initials: M
authors.lastname: Kafri
authors.forename: Karin
authors.initials: K
authors.lastname: Maoz
authors.forename: Batsheva
authors.initials: B
authors.lastname: Kerem
mesh_terms: D002460:Cell Line; D043283:Chromosome Fragile Sites / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics*; D008677:Metaphase; D014162:Transfection; D016662:Virus Integration / Q000235:genetics*