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Deletions in Human 1p36 are among the major chromosomal aberrations associated with human cancers, suggesting the presence of one or more tumor suppressor gene(s) mapping to this locus. Though a plethora of mapping data exists, functional identification of the tumor suppressor(s) has remained notoriously elusive. In this study we undertook a functional genetic approach to devise an in vivo screen , for complimentary gain and loss of function of the locus that harbors the putative tumor suppressor, using chromosome engineering strategy in mouse embryonic stem cells. Using this screen we first identified a 4.3 Mb region in mouse chromosome 4, corresponding to Human 1p36, as a tumor suppressor bearing locus. Then we devised a RNAi based screen that identified Chromodomain helicase DNA binding protein 5 (Chd5) as the tumor suppressor gene in that 4.3 Mb genomic interval. To elucidate the mechanism of tumor suppression by Chd5, we demonstrate that Chd5 positively controls the expression of p16Ink4a and p19Arf. This is the first report of a chromodomain containing chromatin remodeling protein that functions as a tumor suppressor. This work also provides new insights to the expanding role of chromatin remodeling proteins in regulation of gene expression and their potential as therapeutics against tumorigenesis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA