Cancer gene discovery has relied extensively on analyzing tumors for gains and losses to reveal the location of oncogenes and tumor suppressor genes, respectively. Deletions of 1p36 are extremely common genetic lesions in human cancer, occurring in malignancies of epithelial, neural, and hematopoietic origin. Although this suggests that 1p36 harbors a gene that drives tumorigenesis when inactivated, the identity of this tumor suppressor has remained elusive. Here we use chromosome engineering to generate mouse models with gain and loss of a region corresponding to human 1p36. This approach functionally identifies chromodomain helicase DNA binding domain 5 (Chd5) as a tumor suppressor that controls proliferation, apoptosis, and senescence via the p19Arf/p53 pathway. We demonstrate that Chd5 functions as a tumor suppressor in vivo and implicate deletion of CHD5 in human cancer. Identification of this tumor suppressor provides new avenues for exploring innovative clinical interventions for cancer.
Bibliographical noteFunding Information:
We thank Winship Herr, Scott Lowe, Masaashi Narita, and Bruce Stillman for helpful discussions and Darren Burgess for the shp19 construct. We appreciate Sydney Gary and David Spector for reading of the manuscript. We thank Mary Kusenda, Sang Yong Kim, and Lisa Bianco for technical expertise. This project was initiated in Allan Bradley's laboratory at Baylor College of Medicine and was funded by the National Cancer Institute (NCI). It has also been supported by the CSHL Cancer Center support grant from NCI, CA45508.