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• W2726703003 abstract "The cellular response to radiation is governed by a complex signaling network that is regulated by the ubiquitin-proteasome system in multiple ways. The AAA-type ATPase p97 (also known as VCP or Cdc48) has emerged as a central element of the ubiquitin-proteasome system as it facilitates the degradation of critical substrate proteins by the proteasome. As such, it is involved in replication stress and DNA damage responses, and is currently explored as a cancer drug target in clinical trials. However, its function is still poorly understood. p97 cooperates with protein cofactors, three of which have been linked to the radiation response: the heterodimeric Ufd1-Npl4 ubiquitin adapter, DVC1 and UBXD7 that acts as an adapter to cullin-RING ubiquitin ligases (CRLs).This work provides insight into three different aspects of the role of p97 and its cofactors in the response to replication stress and DNA damage in human cells. First, we investigated the relevance of p97 for DNA damage checkpoints. Second, we examined the significance of p97 and its cofactors for survival of human cancer cells after replication stress. Third, we explored the role of a novel p97 cofactor, UBXD7 that was linked to DNA-related functions of p97. Analyses of the G1/S and intra S checkpoints showed that p97Ufd1-Npl4 may only play a minor role in these checkpoints. However, DVC1 is crucial for the intra S checkpoint. Importantly, work from this study contributed to demonstrating that the p97Ufd1-Npl4 complex ensures robustness of the G2/M checkpoint by facilitating the degradation of the phosphatase CDC25A (published in Riemer et al, 2014). This study confirmed the relevant target protein of p97, CDC25A, in the checkpoint and contributed to the identification of the cofactors involved in CDC25A degradation, including the novel p97 cofactor UBXD7. Moreover, we could demonstrate that in mammalian cells, unrepaired DNA damage from interphase manifests in mitotic segregation errors in cells depleted of p97Ufd1-Npl4 and that the lack of either of these components decreased cell survival after replication stress. Furthermore, p97 inhibition with the inhibitor NMS-873 showed a synergistic effect with the genotoxic chemotherapeutic agent doxorubicin. Additionally, NMS-873 was able to delay the degradation of CDC25A in the DNA damage response. Finally, by investigating the significance of UBXD7 for diverse p97 substrate proteins, we found that UBXD7 is not generally involved in CRL- and p97-dependent degradation both in the nucleus and the cytoplasm. Moreover, a detailed structure-function analysis revealed that binding to CRLs and p97 is essential for UBXD7 function." @default.
• W2726703003 created "2017-07-14" @default.
• W2726703003 creator A5054057515 @default.
• W2726703003 date "2016-10-18" @default.
• W2726703003 modified "2023-09-27" @default.
• W2726703003 title "The AAA-ATPase p97 and its cofactors in regulatory degradation of substrate proteins after DNA damage or replication stress" @default.
• W2726703003 hasPublicationYear "2016" @default.
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