A stapled <scp>POL</scp> κ peptide targets <scp>REV1</scp> to inhibit mutagenic translesion synthesis

Chatterjee, Nimrat; D’Souza, Sanjay; Shabab, Mohammad; Harris, Cynthia; Hilinski, Gerard J.; Verdine, Gregory L.; Walker, Graham C.

doi:10.1002/em.22395

Cited by 6 publications

(9 citation statements)

References 19 publications

(27 reference statements)

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“…This could also serve as an opportunity to recruit Pol ζ, which would efficiently extend from the bypassed DNA lesion (13). Importantly, inhibiting the interaction of Rev1 with other TLS polymerases was recently shown as a promising therapeutic target in cancer (40)(41)(42). Therefore, future work is necessary to fully understand the interplay between the nonprocessive nature of Rev1 and the scaffolding function during the polymerase switch.…”

Section: Organization Of Substrates and Products Within The Rev1 Active Sitementioning

confidence: 99%

Visualizing Rev1 catalyze protein-template DNA synthesis

Weaver

Cortez

Khoang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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During DNA replication, replicative DNA polymerases may encounter DNA lesions, which can stall replication forks. One way to prevent replication fork stalling is through the recruitment of specialized translesion synthesis (TLS) polymerases that have evolved to incorporate nucleotides opposite DNA lesions. Rev1 is a specialized TLS polymerase that bypasses abasic sites, as well as minor-groove and exocyclic guanine adducts. Lesion bypass is accomplished using a unique protein-template mechanism in which the templating base is evicted from the DNA helix and the incoming dCTP hydrogen bonds with an arginine side chain of Rev1. To understand the protein-template mechanism at an atomic level, we employed a combination of time-lapse X-ray crystallography, molecular dynamics simulations, and DNA enzymology on the Saccharomyces cerevisiae Rev1 protein. We find that Rev1 evicts the templating base from the DNA helix prior to binding the incoming nucleotide. Binding the incoming nucleotide changes the conformation of the DNA substrate to orient it for nucleotidyl transfer, although this is not coupled to large structural changes in Rev1 like those observed with other DNA polymerases. Moreover, we found that following nucleotide incorporation, Rev1 converts the pyrophosphate product to two monophosphates, which drives the reaction in the forward direction and prevents pyrophosphorolysis. Following nucleotide incorporation, the hydrogen bonds between the incorporated nucleotide and the arginine side chain are broken, but the templating base remains extrahelical. These postcatalytic changes prevent potentially mutagenic processive synthesis by Rev1 and facilitate dissociation of the DNA product from the enzyme.

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Section: Organization Of Substrates and Products Within The Rev1 Active Sitementioning

confidence: 99%

Visualizing Rev1 catalyze protein-template DNA synthesis

Weaver

Cortez

Khoang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…These landmark observations provide a semblance as to why the cancer mutational spectrum continues to evolve and an understanding as to why there remains a continuity to clinical challenges in treating patients. Furthermore, the discovery of REV1 inhibitors provided a reliable platform for potential clinical adjuvant therapy [2][3][4][5] . However, indications that REV1 inhibition can also switch the underlying biology of cancer cells, whereby it can suppress apoptosis in cisplatin-treated cells, and trigger senescence 8 , suggested that REV1 may have a larger new role in cancer pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…This study tested whether REV1 inhibition via CTD-specific small molecule inhibitors sensitizes cancer cells to radiation treatment. In contrast to their chemosensitization effects [2][3][4][5]8 , REV1 inhibition failed to sensitize cancer cells to ionizing radiation. We confirmed the lack of radiosensitization by using five different REV1 inhibitors, varying doses of REV1 inhibitors, testing physiologically relevant increasing ionizing radiation doses, and examining radioresistant cell lines.…”

Section: Introductionmentioning

confidence: 87%

“…REV1 protein plays a crucial role in the DNA damage bypass process by functioning as a scaffolding molecule that facilitates protein-protein interactions with other TLS polymerases via its CTD 1 . Previously, REV1 inhibitors that targeted specific interfaces of this CTD were shown to sensitize cancer cells to chemotherapy treatment, which suggested that the REV1-dependent DNA damage bypass of chemotherapy-induced damage was the cause of chemoresistance [2][3][4][5]8 . Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is currently unknown.…”

Section: Rev1 Inhibition Does Not Sensitize Cancer Cells To Irmentioning

confidence: 99%

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REV1 Inhibition Enhances Radioresistance and Autophagy

Ikeh

Lamkin

Crompton

et al. 2021

Preprint

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Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1’s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. Collectively, we report a possible role of REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with significant bearing on cancer treatment regimens.

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“…Intrinsic and acquired resistance to DNA-damaging cancer therapy is a persistent clinical challenge that ultimately limits successful clinical outcomes in patients [ 1 ]. Recent evidence suggests that a possible strategy to sensitize tumors and reduce chemotherapy resistance is to inhibit the mutagenic translesion synthesis (TLS) pathway by targeting REV1 TLS polymerase [ 2 , 3 , 4 , 5 ]. Translesion synthesis is a DNA damage bypass process involving a set of specialized DNA polymerases that collectively tolerate DNA damage and cause mutations [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

REV1 Inhibition Enhances Radioresistance and Autophagy

Ikeh

Lamkin

Crompton

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1’s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. We report a possible role of the REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover that REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with a significant bearing on cancer treatment regimens.

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A stapled POL κ peptide targets REV1 to inhibit mutagenic translesion synthesis

Cited by 6 publications

References 19 publications

Visualizing Rev1 catalyze protein-template DNA synthesis

Visualizing Rev1 catalyze protein-template DNA synthesis

REV1 Inhibition Enhances Radioresistance and Autophagy

REV1 Inhibition Enhances Radioresistance and Autophagy

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