Abstract
The MRE11/RAD50/NBS1 (MRN) complex mediates DNA repair pathways, including double-strand breaks induced by radiotherapy. Meiotic recombination 11 homolog (MRE11) is downregulated by histone deacetylase inhibition (HDACi), resulting in reduced levels of DNA repair in bladder cancer cells and radiosensitization. In this study, we show that the mechanism of this downregulation is posttranslational and identify a C-terminally truncated MRE11, which is formed after HDAC inhibition as full-length MRE11 is downregulated. Truncated MRE11 was stabilized by proteasome inhibition, exhibited a decreased half-life after treatment with panobinostat, and therefore represents a newly identified intermediate induced and degraded in response to HDAC inhibition. The E3 ligase cellular inhibitor of apoptosis protein 2 (cIAP2) was upregulated in response to HDAC inhibition and was validated as a new MRE11 binding partner whose upregulation had similar effects to HDAC inhibition. cIAP2 overexpression resulted in downregulation and altered ubiquitination patterns of MRE11 and mediated radiosensitization in response to HDAC inhibition. These results highlight cIAP2 as a player in the DNA damage response as a posttranscriptional regulator of MRE11 and identify cIAP2 as a potential target for biomarker discovery or chemoradiation strategies in bladder cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 3027-3029 |
| Number of pages | 3 |
| Journal | Cancer Research |
| Volume | 77 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 1 Jun 2017 |
Bibliographical note
Funding Information:We thank Dr. Roman Fischer, head of the Advanced Proteomics Facility within the TDI Mass Spectrometry Laboratory, for technical expertise and advice on mass spectrometry. We thank Dr. Euan Murray for generously providing His-Ub plasmid. This work was funded by CRUK Programme grant C5255/A15935 to A.E. Kiltie, an MRC studentship to S. Jevons, the John Fell Fund133/075 to B.M. Kessler, and Wellcome Trust grant 097813/Z to B.M. Kessler.
Publisher Copyright:
©2017 AACR.
