International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 153 - STUDY OF RECQ DNA HELICASE FUNCTION AND RELATED HUMAN DISORDERS USING MOUSE MODELS

M Mann
Case Western Reserve University

1) Barnes E, 2) Bradley A, 1) Luo G
1) Case Western Reserve University, 2) The Sanger Centre

The RecQ DNA helicase genes encode a class of conserved proteins in diverged organisms, from bacteria and yeast to humans.  Loss-of-function mutations in three of the five known human RecQ helicase genes, BLM, WRN, and RECQL4, cause three autosomal recessive human syndromes, Bloom (BS), Werner (WS), and Rothmund-Thompson (RTS), respectively.  Each of these syndromes manifests a multitude of clinical phenotypes, many of which are unique to a specific disorder.  Yet despite this, they also share the common themes of premature aging, genomic instability and cancer predisposition.  The presentation of both common and distinctive features in these three syndromes suggests that, in mammals, the individual RecQ helicase proteins have acquired non-redundant functions, while maintaining conserved biochemical properties.We are using the mouse as a model system to address the function of mammalian RecQ DNA helicases.  Previously, we have reported a Blm mouse model which recapitulates many key phenotypes of BS.  We are expanding upon our studies of the RecQ DNA helicase gene family to include functional studies of Recql4.  To this end, we have created Recql4 mutant mice that harbor a deletion mutation that abolishes the conserved RecQ DNA helicase motif.  Preliminary data with Recql4-difficent ES cells suggest that they are sensitive to ultraviolet C irradiation, a distinct feature of RTS, suggesting that Recql4 participates in the nucleotide excision repair pathway.  Furthermore, we have begun to examine cancer susceptibility of the Recql4 mutant mice as well as the possible genetic interaction between individual murine RecQ DNA helicase homologues.


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