6c8c
From Proteopedia
Chimeric Pol kappa RIR Rev1 C-terminal domain in complex with JHRE06
Structural highlights
Function[POLK_MOUSE] DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Depending on the context, it inserts the correct base, but causes frequent base transitions, transversions and frameshifts. Lacks 3'-5' proofreading exonuclease activity. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity (By similarity).[1] Publication Abstract from PubMedIntrinsic 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 zeta. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL zeta. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL zeta 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 Targeting Mutagenic Translesion Synthesis Improves Chemotherapy.,Wojtaszek JL, Chatterjee N, Najeeb J, Ramos A, Lee M, Bian K, Xue JY, Fenton BA, Park H, Li D, Hemann MT, Hong J, Walker GC, Zhou P Cell. 2019 Jun 4. pii: S0092-8674(19)30556-2. doi: 10.1016/j.cell.2019.05.028. PMID:31178121[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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