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Human DDX11 and DDX12 are closely related genes encoding the helicases ChlR1 and ChlR2, which belong to the CHL1 DNA helicase family. Recently, it was shown that human ChlR1 interacts with components of the cohesin complex and is required for proper centromeric cohesion. To establish the function of ChlR1 in development we made a mutant mouse lacking Ddx11, the single mouse ChlR gene. The absence of Ddx11 resulted in embryonic lethality at E10.5. The mutant embryos were smaller in size, malformed and exhibited sparse cellularity in comparison to normal or heterozygous litter mates. Importantly, loss of Ddx11 resulted in the inability to form a proper placenta, indicating that ChlR1 is essential for placental formation. Detailed analysis of cells isolated from Ddx11-/- embryos revealed a G2/M cell cycle delay, an increased frequency of chromosome missegregation, decreased chromosome cohesion, and increased aneuploidy. To examine whether ChlR proteins are required for arm cohesion and for loading of the cohesin complex, further studies were preformed in ChlR1 siRNA treated cells. These studies revealed that ChlR1 is required for proper sister chromatid arm cohesion and that cohesin complexes bind more loosely to chromatin in the absence of ChlR1. Taken together, these studies provide the first data indicating that the ChlR1 helicase is essential for proper binding of the cohesin complex to both the centromere and the chromosome arms, and indicate that ChlR1 is essential for embryonic development and the prevention of aneuploidy in mammals.
In vitro sister chromatid exchange (SCE) and chromosome aberration (ABS) tests have been extensively used to identify potential rodent carcinogens. A number of measures of potency were developed to describe in vitro SCE and ABS test results: the dose needed to induce a unit increase over the control; the lowest effective dose; the slope of the ordinary linear regression; the maximum observed slope; and the maximum fold increase over background. The ability of these potency measures to predict the qualitative and quantitative carcinogenicity of chemicals was compared to the predictivity of the qualitative in vitro responses. The results of the analyses showed that the quantitative measures of the SCE or ABS responses only minimally increased the predictivity of carcinogenesis when compared to the predictivity using the qualitative responses.