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

被引：7

作者：

Bester, Assaf C. ^{[1
]}

Kafri, Moshe ^{[1
]}

Maoz, Karin ^{[1
]}

Kerem, Batsheva ^{[1
]}

机构：

[1] Hebrew Univ Jerusalem, Inst Life Sci, Dept Genet, IL-91904 Jerusalem, Israel

来源：

SCIENTIFIC REPORTS | 2013年 / 3卷

基金：

以色列科学基金会;

关键词：

ONCOGENE-INDUCED SENESCENCE; GENOMIC INSTABILITY; GENE AMPLIFICATION; DAMAGE RESPONSE; COPY NUMBER; LEUKEMIA; POLYMERASE; SCID-X1; TARGETS; CELLS;

D O I：

10.1038/srep02189

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：8

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