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Transforming growth factor-β (TGFβ) is a well-known master regulator of cellular proliferation and is a critical factor in the maintenance of tissue homeostasis. TGFβ is classically defined as a tumor suppressor that functions in the early stages of carcinogenesis, yet paradoxically it functions as a tumor promoter in established cancers. Less well studied is its role in maintaining genomic stability through its participation in the DNA damage response (DDR). Deletion of Tgfb1 in murine epithelium increases genomic instability (GIN) as measured by gene amplification, aneuploidy, and centrosome aberrations; likewise, GIN is increased by depleting the TGFβ ligand or inhibiting TGFβ pathway signaling in human epithelial cells. Subsequent studies demonstrated that TGFβ depletion compromises cell survival in response to radiation and impairs activation of the DDR because of severely reduced activity of ataxia telangiectasia mutated (ATM), a serine/threonine protein kinase that is rapidly activated by DNA double-strand breaks. The SMAD transcription factors are intermediaries in the crosstalk between the TGFβ and ATM pathways in the DDR. Recent studies have shown that SMAD2 and SMAD7 participate in the DDR in a manner dependent on ATM or TGFβ receptor type I, respectively, in human fibroblasts and epithelial cells. Understanding the role of TGFβ in the DDR and suppressing GIN is important to understanding its seemingly paradoxical roles in tumorigenesis and thus has therapeutic implications for improving the response to DNA damage-inducing therapy.
Barcellos‐Hoff et al. (Tue,) studied this question.