Multipotent hematopoietic cells susceptible to alternative double-strand break repair pathways that promote genome rearrangements

被引:28
作者
Francis, Richard [1 ]
Richardson, Christine [1 ]
机构
[1] Columbia Univ, Dept Pathol, Inst Canc Genet, New York, NY 10032 USA
关键词
double-strand break; homologous recombination; hematopoietic stem cell; chromosomal translocation; genome stability; Rad51;
D O I
10.1101/gad.1522807
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Chromosomal translocations are a hallmark of hematopoietic malignancies. The initial molecular events or pathways that lead to translocations in hematopoietic cells are largely unknown, particularly in the stem cell-enriched population postulated to be the initial target for these events. We used in vitro differentiation of mouse embryonic stem (ES) cells combined with an I-SceI endonuclease double-strand break (DSB) repair assay to determine the relative susceptibility of isogenic hematopoietic subpopulations to DSB-induced translocations and the mechanisms that generate them. DSB-induced reciprocal translocations were frequently observed in multipotent progenitors but significantly suppressed in actively proliferating myeloid cells. Most reciprocal translocations in multipotent progenitors resulted from repair consistent with single-strand annealing followed by gap repair. Overexpression of Rad51, a protein central to DNA strand exchange and recombination, did not further increase the frequency of recovered translocations but did increase the frequency of long-tract gene conversion events associated with loss of heterozygosity and tandem duplications. These data directly demonstrate that hematopoietic multipotent progenitor cells are particularly susceptible to the formation of chromosomal rearrangements analogous to those observed in human hematopoietic malignancies. This particular subpopulation apparently represents a window of opportunity for the initiation of potentially oncogenic events following DNA damage.
引用
收藏
页码:1064 / 1074
页数:11
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