pSer784-VCP: a clinically relevant link between autophagy and DNA damage response

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PROJECT SUMMARY Autophagy and DNA damage response (DDR) are two evolutionarily conserved, fundamentally important cellular programs. Both can be deregulated in cancer and in turn targeted as cancer therapies. Despite compelling evidence that autophagy and DDR are connected, the scarce number of known DDR-relevant autophagy targets greatly limits our understanding of their functional crosstalk. Mixed reports regarding the chemotherapy-sensitizing effect of autophagy activation strongly suggest the context-dependency of the physiological role of autophagy in DDR. We hypothesize that this context-dependency could be determined by the functional importance of the affected autophagy targets for DDR. In this grant, we focus on an important DDR factor named VCP. VCP is a ubiquitously expressed AAA+ ATPase which recognizes polyubiquitinated proteins and facilitates their degradation by both the ubiquitin-proteasome and autophagy/lysosome pathways. Our recent work showed that DNA damage-induced Ser784 phosphorylation selectively increases nuclear VCP function for DDR. Importantly, pSer784-VCP is poor prognostic marker for chemotherapy-treated breast cancer patients. These data suggest that targeting pSer784-VCP may be a novel and effective chemo-sensitizing approach. In this grant, we present preliminary data showing that pSer784-VCP may be a previously unrecognized target of autophagy. In Aim 1, we will define the specific autophagy pathway that is involved in pSer784-VCP degradation and seek for direct evidence that pSer784-VCP undergoes nuclear export upon DNA damage. In Aim 2, we will test in a large panel of triple-negative breast cancer cell lines whether DNA damage-induced pSer784-VCP levels predict chemo-sensitizing effects of autophagy modulators. Together, these experiments will improve our understanding of the functional crosstalk between autophagy and DDR, and help define the biological context within which co-targeting of these two cellular programs can be therapeutically beneficial.