Requirement of Bccip for the Regeneration of Intestinal Progenitors

摘要

BCCIP was originally identified as a BRCA2 and CDKN1A/p21 interaction protein. Although a partial loss of BCCIP function is sufficient to trigger genomic instability and tumorigenesis, complete deletion of BCCIP is lethal to cells. Using Rosa26-CreERT2 mouse models, we found that induced Bccip deletion in adult mice caused an acute intestinal epithelial denudation that cannot be relieved by co-deletion of Trp53. The critical role of Bccip in intestine epithelial renewal was verified with a Villin-CreERT2 mouse model. The epithelium degeneration was associated with a rapid loss of the proliferative capability of the crypt progenitor cells in vivo, lack of crypt base columnar stem cell markers, and a failure of in vitro crypt organoid growth. RNA-Seq analysis of freshly isolated intestinal crypt cells showed that Bccip deletion caused an overwhelming down-regulation of genes involved in mitotic cell division but an upregulation of genes involved in apoptosis and stress response to microbiomes. Our data not only indicate that intestinal epithelium is the most sensitive tissue to whole-body deletion of Bccip but also point to Bccip as a novel and critical factor for the proliferation of the intestinal progenitors. These findings have significant implications for understanding why a hypomorphic loss of BCCIP functions is more relevant to tumorigenesis.