A crypt-operating DNA repair checkpoint for uncoupling regeneration and tumorigenesis

The rapid turnover of the intestinal epithelium increases its vulnerability to genomic instability and environmental insults such as irradiation. Defects in DNA damage resolution can compromise epithelial regeneration, promote chronic tissue injury, and predispose to colorectal tumorigenesis. However, the intrinsic mechanisms that coordinate DNA repair with epithelial regeneration at the crypt level remain poorly defined. Here, we identify the Nod-like receptor protein 6 (Nlrp6) as a key epithelial regulator of genome surveillance and regenerative control in intestinal crypts. Nlrp6 is strategically expressed in crypt base columnar cells, where it preserves crypt homeostasis by restraining proliferation under genotoxic stress conditions. Loss of Nlrp6 in crypt base columnar cells results in uncontrolled oncogenic stress, defective epithelial regeneration, and accumulation of unrepaired DNA damage, features associated with poor prognosis in colorectal cancer. Conversely, aberrant Nlrp6 overexpression induces cytoplasmic retention of Csnk2 catalytic subunits, limiting their nuclear availability when DNA repair is required. These findings position Nlrp6 as a non-canonical, cell-intrinsic surveillance mechanism that links DNA damage responses to epithelial regeneration through Csnk2-dependent signaling. Collectively, our study reveals a crypt-intrinsic DNA repair pathway that governs epithelial regeneration and disease outcomes, providing new insight into how genome instability and regenerative failure contribute to colorectal cancer progression.