Infection with retroviral vectors leads to perturbed DNA replication increasing vector integrations into fragile sites

Assaf C. Bester, Moshe Kafri, Karin Maoz, Batsheva Kerem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageAmerican English
Article number2189
JournalScientific Reports
Volume3
DOIs
StatePublished - 2013

Bibliographical note

Funding Information:
This study was partially supported by the Israel Association for Cancer Research and the I-CORE Program of the Planning and Budgeting Committee and the Israel Science Foundation (grant No 41/11) to B.K. The authors wish to thank Prof. Moshe Y. Flugelman (Technion, Israel) and Prof. Bertrand Boson (Université de Lyon, Lyon, France) for the MLV-based vectors and Dr. Naomi Melamed-Book from the confocal microscopy unit of the Hebrew University for assistance in the microscopic analyses.

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