DNA Damage Activates TGF-β Signaling via ATM-c-Cbl-Mediated Stabilization of the Type II Receptor TβRII

Abstract

Activation of both the DNA damage response (DDR) and transforming growth factor β (TGF-β) signaling induces growth arrest of most cell types. However, it is unclear whether the DDR activates TGF-β signaling that in turn contributes to cell growth arrest. Here, we show that in response to DNA damage, ataxia telangiectasia mutated (ATM) stabilizes the TGF-β type II receptor (TβRII) and thus enhancement of TGF-β signaling. Mechanistically, ATM phosphorylates and stabilizes c-Cbl, which promotes TβRII neddylation and prevents its ubiquitination-dependent degradation. Consistently, DNA damage enhances the interaction among ATM, c-Cbl, and TβRII. The ATM-c-Cbl-TβRII axis plays a pivotal role in intestinal regeneration after X-ray-induced DNA damage in mouse models. Therefore, ATM not only mediates the canonical DDR pathway but also activates TGF-β signaling by stabilizing TβRII. The double brake system ensures full cell-cycle arrest, allowing efficient DNA damage repair and avoiding passage of the damaged genome to the daughter cells.

Keywords: ATM; DNA damage; TGF-β signaling; TβRII; c-Cbl.