A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy
Name
nihms-1531081.pdf
Description
Accepted version
Size
1.23 MB
Format
Unknown
Checksum (MD5)
b904115c69b4cfd898fe56ed5f758bf0
Author(s)
Wojtaszek, Jessica L.
Chatterjee, Nimrat
Najeeb, Javaria
Ramos, Azucena
Lee, Minhee
Bian, Ke
Xue, Jenny Y.
Fenton, Benjamin A.
Park, Hyeri
Li, Deyu
Date Issued
June 2019
Journal
Cell
Publisher
Elsevier BV
Version
Author's final manuscript
Abstract
© 2019 Elsevier Inc. Intrinsic and acquired drug resistance and induction of secondary malignancies limit successful chemotherapy. Because mutagenic translesion synthesis (TLS) contributes to chemoresistance as well as treatment-induced mutations, targeting TLS is an attractive avenue for improving chemotherapeutics. However, development of small molecules with high specificity and in vivo efficacy for mutagenic TLS has been challenging. Here, we report the discovery of a small-molecule inhibitor, JH-RE-06, that disrupts mutagenic TLS by preventing recruitment of mutagenic POL ζ. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL ζ. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL ζ recruitment. JH-RE-06 inhibits mutagenic TLS and enhances cisplatin-induced toxicity in cultured human and mouse cell lines. Co-administration of JH-RE-06 with cisplatin suppresses the growth of xenograft human melanomas in mice, establishing a framework for developing TLS inhibitors as a novel class of chemotherapy adjuvants. A small molecule specifically targeting the mutagenic branch of translesion synthesis binds a nearly featureless surface of REV1 to induce dimerization and block recruitment of POL ζ.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.cell.2019.05.028
