Yeast Smy2 and its human homologs GIGYF1 and -2 regulate Cdc48/VCP function during transcription stress
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The “last resort” pathway results in ubiquitylation and degradation of RNA polymerase II in response to transcription stress and is governed by factors such as Def1 in yeast. Here, we show that the SMY2 gene acts as a multi-copy suppressor of DEF1 deletion and functions at multiple steps of the last resort pathway. We also provide genetic and biochemical evidence from disparate cellular processes that Smy2 works more broadly as a hitherto overlooked regulator of Cdc48 function. Similarly, the Smy2 homologs GIGYF1 and -2 affect the transcription stress response in human cells and regulate the function of the Cdc48 homolog VCP/p97, presently being explored as a target for cancer therapy. Indeed, we show that the apoptosis-inducing effect of VCP inhibitors NMS-873 and CB-5083 is GIGYF1/2 dependent.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 111536 |
| Tidsskrift | Cell Reports |
| Vol/bind | 41 |
| Udgave nummer | 4 |
| ISSN | 2211-1247 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This work was supported by the Francis Crick Institute (FCI receives funding from Cancer Research UK [ FC001166 ], the UK Medical Research Council [ FC001166 ], and the Wellcome Trust [ FC001166 ]) and by grants to J.Q.S. from the European Research Council (ERC Agreement 693327 ), a Laureate grant from the Novo Nordisk Foundation ( NNF19OC0055875 ), and a Chair grant from the Danish National Research Foundation ( DNRF153 ). We thank FCI’s Cell Services and Mass Spectrometry as well as Stefan Boeing for expert technical assistance; Crick Flow Cytometry Platform for help with GFP cell sorting and Mary Wu and Michael Howell of the Crick High Throughput Screening Platform for Incucyte data collection; Svejstrup lab members for discussions; and Peter Verrijzer for helpful comments on the manuscript. Anouk Olthof is thanked for her help with the graphical abstract.
Funding Information:
This work was supported by the Francis Crick Institute (FCI receives funding from Cancer Research UK [FC001166], the UK Medical Research Council [FC001166], and the Wellcome Trust [FC001166]) and by grants to J.Q.S. from the European Research Council (ERC Agreement 693327), a Laureate grant from the Novo Nordisk Foundation (NNF19OC0055875), and a Chair grant from the Danish National Research Foundation (DNRF153). We thank FCI's Cell Services and Mass Spectrometry as well as Stefan Boeing for expert technical assistance; Crick Flow Cytometry Platform for help with GFP cell sorting and Mary Wu and Michael Howell of the Crick High Throughput Screening Platform for Incucyte data collection; Svejstrup lab members for discussions; and Peter Verrijzer for helpful comments on the manuscript. Anouk Olthof is thanked for her help with the graphical abstract. M.H.L. and J.Q.S. conceived the project. M.H.L. performed most of the experiments with contributions from J.W. (generation of human cell lines; drug sensitivity experiments), K.T. (Ubx experiments), A.H. (PLA experiments), M.T. (Smy2 purification), and A.C.B. (DEF1 suppressor screen). A.H.C. and J.Q.S. supervised the work. M.H.L. A.B.D.S. and J.Q.S. wrote the manuscript, with input from other authors. The authors declare no competing interests.
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© 2022 The Authors
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