A divergent Slfn-mediated DNA damage response in human and mice
In response to DNA damage SLFN11 was demonstrated to induce UUA ribosome stalling and consequent apoptosis, independently of p53. The clinical relevance of this finding is suggested by the fact that SLFN11 expression is one of the strongest biomarkers for chemosensitivity in human tumors. Because mice are frequently used to model the development and treatment of cancer we sought to determine if they exhibit a Slfn-dependent response to DNA damage. SLFN11 and murine Slfn9 - the closest homologue of SLFN11 - become active in response to transfected ssDNA, leading to ribosome stalling and activation of the ribotoxic stress response. In contrast, DNA damage, a potent activating signal for human SLFN11, did not activate murine Slfn9 nor triggered ribosome stalling. These observations suggest that a frequently used animal model for cancer research lacks an important response to DNA damage that may affect both treatment outcome as well as unwanted therapy-induced side effects in patients.
In response to DNA damage SLFN11 was demonstrated to induce UUA ribosome stalling and consequent apoptosis, independently of p53. The clinical relevance of this finding is suggested by the fact that SLFN11 expression is one of the strongest biomarkers for chemosensitivity in human tumors. Because mice are frequently used to model the development and treatment of cancer we sought to determine if they exhibit a Slfn-dependent response to DNA damage. SLFN11 and murine Slfn9 - the closest homologue of SLFN11 - become active in response to transfected ssDNA, leading to ribosome stalling and activation of the ribotoxic stress response. In contrast, DNA damage, a potent activating signal for human SLFN11, did not activate murine Slfn9 nor triggered ribosome stalling. These observations suggest that a frequently used animal model for cancer research lacks an important response to DNA damage that may affect both treatment outcome as well as unwanted therapy-induced side effects in patients.
Antoni van Leeuwenhoek - Netherlands Cancer Institute