Disease relevance of Blm

• The proportional dwarfism seen in the human is consistent with the small size and developmental delay (12-24 hr) seen during mid-gestation in murine Blm-/- embryos [1].
• Blm-deficient mice, like Bloom syndrome patients, have increased frequencies of mitotic recombination owing to a mutation in the RecQ protein-like-3 helicase gene [2].

High impact information on Blm

• Red blood cells and their precursors from Blm-/- embryos are heterogeneous in appearance and have increased numbers of macrocytes and micronuclei [1].
• Tumor suppressor gene identification using retroviral insertional mutagenesis in Blm-deficient mice [2].
• We also show that known as well as novel TS genes can be identified by insertional mutagenesis in Blm-deficient mice and identify two JmjC family proteins that contribute to genome stability in species as evolutionarily diverse as mammals and Caenorhabditis elegans [2].
• We used a novel two-step analysis to investigate a panel of eight cell lines developed from mammary tumors that appeared in Blm conditional knockout mice [3].
• Thus, this study identifies a previously unknown Recql5-dependent, Blm-independent pathway for suppressing crossovers during mitosis in mice [4].

Biological context of Blm

• We recently reported genome-wide bi-allelic mutagenesis and phenotype-based genetic screening by tetracycline-regulated disruption of the Bloom's syndrome gene (Blm) in mouse embryonic stem (ES) cells [5].
• The system was applied to mouse splenic lymphocytes and elevation of sister chromatid exchange, the hallmark of Blm dysfunction, was observed in the presence of doxycycline [5].
• Here we show that TS genes can be identified by insertional mutagenesis when the screens are performed in Blm-deficient backgrounds [2].
• Induction of renal tumorigenesis with elevated levels of somatic loss of heterozygosity in Tsc1+/- mice on a Blm-deficient background [6].
• Our results suggest that Wrn, Blm, and RecQ1 are not involved in sequence-specific mRNA degradation in mammals in response to dsRNA, suggesting potential differences in the mammalian RNAi pathway [7].

Anatomical context of Blm

• Embryonic stem cells deficient for Brca2 or Blm exhibit divergent genotoxic profiles that support opposing activities during homologous recombination [8].
• The mBLM mRNA level in the testis began to increase 12-14 days after birth, corresponding to the appearance of cells in the pachytene phase [9].

Associations of Blm with chemical compounds

• However, the same approach was hampered in mouse tissues owing to leaky expression of the Blm gene, which is the major obstacle in the tetracycline regulatory system [5].
• A cassette containing both sc rtTS and tTA was introduced into the Blm allele in ES cells and reduction of basal activity was observed upon doxycycline treatment [5].
• By contrast, Blm-impaired cells are hypersensitive to ICRF-193, mildly resistant to camptothecin and mitomycin C and more strongly resistant to hydroxyurea [8].
• Indeed, a combination of N-ethyl-N-nitrosourea mutagenesis and transient loss of Blm expression enabled us to generate an ES cell library with genome-wide bi-allelic mutations [10].

Other interactions of Blm

• Mismatch repair genes identified using genetic screens in Blm-deficient embryonic stem cells [11].

References