Cancer predisposition caused by elevated mitotic recombination in Bloom mice

  title={Cancer predisposition caused by elevated mitotic recombination in Bloom mice},
  author={Guangbin Luo and Irma M. Santoro and Lisa D. McDaniel and Ichiko Nishijima and Michael Mills and Hagop Youssoufian and Hannes Vogel and Roger A. Schultz and Allan Bradley},
  journal={Nature Genetics},
Bloom syndrome is a disorder associated with genomic instability that causes affected people to be prone to cancer. Bloom cell lines show increased sister chromatid exchange, yet are proficient in the repair of various DNA lesions. The underlying cause of this disease are mutations in a gene encoding a RECQ DNA helicase. Using embryonic stem cell technology, we have generated viable Bloom mice that are prone to a wide variety of cancers. Cell lines from these mice show elevations in the rates… 
Enhanced Tumor Formation in Mice Heterozygous for Blm Mutation
Observations indicate that Blmis a modifier of tumor formation in the mouse and that Blmhaploinsufficiency is associated with tumor predisposition, a finding with important implications for cancer risk in humans.
Mutation of the Murine Bloom's Syndrome Gene Produces Global Genome Destabilization
Results show that Blm gene mutation produces chromosomal instability, strengthening a role for CIN in the development of human cancer.
Hyper-recombination and genetic instability in BLM-deficient epithelial cells.
Surprisingly, BLM-deficient colorectal cancer epithelial cells did not display gross chromosomal rearrangements nor a change in the rates of chromosome gains and losses, however, the enhanced homologous recombination was associated with losses of heterozygosity.
Enhancement of microhomology-mediated genomic rearrangements by transient loss of mouse Bloom syndrome helicase.
The experimental approach successfully uncovered the detailed molecular mechanisms of as-yet-uncharacterized loss of heterozygosities and reveals the significant contribution of microhomology-mediated genomic rearrangements, which could be widely applicable to the early steps of cancer formation in general.
Genomic instability and cancer: lessons from analysis of Bloom's syndrome.
The present article begins by introducing BLM and its binding partners before reviewing its known biochemical activities and its potential roles both as a pro-recombinase and as a suppressor of homologous recombination.
Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome.
Observations provide evidence for a previously unsuspected role for Recql4 in sister-chromatid cohesion, and suggest that the chromosomal instability may be the underlying cause of cancer predisposition and birth defects in these mutant mice.
Deficiency of Bloom syndrome helicase activity is radiomimetic
It is shown that BLM-knockout colorectal cancer cells exhibited endogenous, ATM-dependent double-strand DNA break responses similar to those recently observed in Bloom syndrome patient-derived cells, suggesting that pharmacological inhibitors of BLM would have a radiomimetic effect, and that transient inhibition of BLM activity might be a viable strategy for anticancer therapy.
The Bloom's syndrome helicase suppresses crossing over during homologous recombination
It is shown that mutations in BLM and hTOPO IIIα together effect the resolution of a recombination intermediate containing a double Holliday junction and prevents exchange of flanking sequences, which has wider implications for the understanding of the process of homologous recombination and the mechanisms that exist to prevent tumorigenesis.
Carcinogens induce genome-wide loss of heterozygosity in normal stem cells without persistent chromosomal instability.
It is suggested that LOH contributes significantly to the carcinogenicity of a variety of mutagens and raises the possibility that genome-wide LOH observed in some human cancers may reflect prior exposure to genotoxic agents rather than a state of chromosomal instability during the carcinogenic process.


Manipulation of the mouse germline in the study of Min-induced neoplasia.
To identify other genes in the pathway(s) of intestinal tumorigenesis, genes that modify the Min phenotype have been sought and several have been identified, including Mom1 and the genes for the 5-cytosine DNA methyltransferase and the DNA mismatch repair factor Msh2.
Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome
It is reported that three RTS patients carried two types of compound heterozygous mutations in RECQL4, which suggests that mutation ofRECQL4 at human chromosome 8q24.3 is responsible for at least some cases of RTS.
The Bloom's syndrome gene product is homologous to RecQ helicases
Bloom Syndrome: A Mendelian Prototype of Somatic Mutational Disease
The following aspects of BS are discussed: the BS phenotype; neoplasia in BS, including the means--the Bloom's Syndrome Registry--by which the significant risk for diverse sites and types of cancer in these patients was revealed; the biological basis for the cancer proneness of BS; and the significance of BS as the prototype of somatic mutational disease.
Sister Chromatid Exchanges Are Mediated by Homologous Recombination in Vertebrate Cells
Findings show that HR uses the nascent sister chromatid to repair potentially lethal DNA lesions accompanying replication, which might explain the lethality or tumorigenic potential associated with defects in HR or HR-associated proteins.
Fission Yeast rad12+Regulates Cell Cycle Checkpoint Control and Is Homologous to the Bloom’s Syndrome Disease Gene
The cloning of rad12+, which is the fission yeast homolog of Bloom’s syndrome and is identical to the recently reportedrhq1 + gene, is described and genetically and biochemically it is shown that rad12null cells are sensitive to DNA damage induced by UV light and γ radiation, as well as to the DNA synthesis inhibitor hydroxyurea.
Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation.
  • G. Luo, M. Yao, J. Petrini
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
The null mrad50 mutation is lethal in cultured embryonic stem cells and in early developing embryos, indicating that the mammalian Mre11/Rad50 protein complex mediates functions in normally growing cells that are essential for viability.
rqh1+, a fission yeast gene related to the Bloom‘s and Werner's syndrome genes, is required for reversible S phase arrest
It is shown that, like BLM and SGS1, rqh1+ is required to prevent recombination and that in fission yeast suppression of inappropriate recombination is essential for reversible S phase arrest.
Defending genome integrity during DNA replication: a proposed role for RecQ family helicases
It is proposed that RecQ helicases are required for ensuring that structural abnormalities arising during replication, such as at sites where replication forks encounter DNA lesions, are corrected with high fidelity.