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Cited by 12DNA Repair MechanismsNonmelanoma Skin Cancer StudiesSkin Protection and Aging

Modulation of UVB-induced Carcinogenesis by Activation of Alternative DNA Repair Pathways

Open access
Sha, Yan, Vartanian, Vladimir, Owen, Nichole, Mengden Koon, Stephanie J., Calkins, Marcus J., Thompson, Courtney S., Mirafzali, Zahra, Mir, Sara +9 more·2018·Scientific Reports
DOI 10.1038/s41598-017-17940-8PMC PMC5768739
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Abstract

The molecular basis for ultraviolet (UV) light-induced nonmelanoma and melanoma skin cancers centers on cumulative genomic instability caused by inefficient DNA repair of dipyrimidine photoproducts. Inefficient DNA repair and subsequent translesion replication past these DNA lesions generate distinct molecular signatures of tandem CC to TT and C to T transitions at dipyrimidine sites. Since previous efforts to develop experimental strategies to enhance the repair capacity of basal keratinocytes have been limited, we have engineered the N-terminally truncated form (Δ228) UV endonuclease (UVDE) from Schizosaccharomyces pombe to include a TAT cell-penetrating peptide sequence with or without a nuclear localization signal (NLS): UVDE-TAT and UVDE-NLS-TAT. Further, a NLS was engineered onto a pyrimidine dimer glycosylase from Paramecium bursaria chlorella virus-1 (cv-pdg-NLS). Purified enzymes were encapsulated into liposomes and topically delivered to the dorsal surface of SKH1 hairless mice in a UVB-induced carcinogenesis study. Total tumor burden was significantly reduced in mice receiving either UVDE-TAT or UVDE-NLS-TAT versus control empty liposomes and time to death was significantly reduced with the UVDE-NLS-TAT. These data suggest that efficient delivery of exogenous enzymes for the initiation of repair of UVB-induced DNA damage may protect from UVB induction of squamous and basal cell carcinomas.

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AI snapshot

Written from the paper’s full text.

TL;DR

Topical liposomal delivery of engineered UV repair enzymes (UVDE-TAT, UVDE-NLS-TAT, cv-pdg-NLS) was tested in UVB-irradiated SKH1 hairless mice. UVDE-TAT and UVDE-NLS-TAT reduced total tumor burden at 33 weeks, and UVDE-NLS-TAT significantly reduced tumor-induced euthanasia risk.

Key findings

  • At 33 weeks, mean total tumor size per mouse was ~25 mm in controls, ~12 mm in both UVDE groups, and 18.3 mm in cv-pdg-NLS; reductions were significant for UVDE-TAT (p = 0.041) and UVDE-NLS-TAT (p = 0.045), but not cv-pdg-NLS (p = 0.541).
  • Time to first 2 mm tumor was not significantly delayed: p = 0.404 for UVDE-TAT, 0.788 for UVDE-NLS-TAT, and 0.668 for cv-pdg-NLS.
  • UVDE-NLS-TAT reduced risk of tumor-induced euthanasia: Cox HR 0.25 (95% CI 0.07–0.81), corresponding to 75% less risk than controls; log-rank p = 0.037. UVDE-TAT log-rank p = 0.135 and cv-pdg-NLS p = 0.598.
  • At 23 weeks, control mice had 28 tumors with aggregate size 122 mm, versus 18 tumors/29 mm for UVDE-TAT, 15 tumors/21 mm for UVDE-NLS-TAT, and 19 tumors/42 mm for cv-pdg-NLS; histology of tumors was indistinguishable among groups and characteristic of SCCs.

Methods

  • Engineered Δ228 UVDE from *Schizosaccharomyces pombe* with TAT and/or NLS, and cv-pdg with NLS; proteins were expressed, purified, and encapsulated into liposomes at 10 μg/mL in a 0.75% hydrogel.
  • 40 SKH1 hairless mice were assigned to 4 groups (10 each): empty liposome control, UVDE-TAT, UVDE-NLS-TAT, or cv-pdg-NLS; an additional 10 untreated mice developed no spontaneous tumors. Liposomes (0.2 mL) were applied topically 1 hr before UVB; after 9 acclimation exposures totaling 2.0 kJ/m² over 3 weeks, mice received ~22 kJ/m²/week for 30 additional weeks.
  • Outcomes included time to first 2 mm tumor, total tumor burden at 23 and 33 weeks, and time-to-death; analyses used Kaplan-Meier/log-rank tests, Cox regression, and ANOVA with Tukey-adjusted pairwise comparisons.

Limitations

  • The paper states that using final observed tumor values for euthanized mice underestimates total tumor burden because it does not account for anticipated continued tumor growth.
  • The paper states that mechanisms of UVDE-mediated reduction in carcinogenesis were not explicitly tested in this investigation.
  • Evident from the text: each treatment group had only 10 mice, and the study was limited to a mouse model without human clinical validation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41598-017-17940-8

Cites

42 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 36 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Time to first 2 mm tumor did not differ significantly between active enzyme groups and control, with p-values 0.404 for UVDE-TAT, 0.788 for UVDE-NLS-TAT, and 0.668 for cv-pdg-NLS.

    “these delays were not statistically distinguishable from the control group, with nonsignificant p-values of 0.404 for UVDE-TAT, 0.788 for UVDE-NLS-TAT, and 0.668 for cv-pdg-NLS.”
    Quote in the paperSubstantial claim
  • Findingown data

    Comparable analysis of cv-pdg-NLS compared to controls revealed less of a survival advantage (p = 0.598) than was observed for the two UVDE groups.

    “A comparable analysis of another encapsulated enzyme compared to controls (Fig. 5b) revealed less of a survival advantages for cv-pdg-NLS (p = 0.598) than was observed for the two UVDE groups.”
    Quote in the paperSubstantial claim
  • Findingown data

    At 23 weeks, mean total tumor size per mouse for empty, UVDE-TAT, UVDE-NLS-TAT, and cv-pdg-NLS liposome-treated groups were 12.2 mm, 2.9 mm, 2.1 mm, and 4.2 mm, respectively.

    “At 23 weeks, the mean total tumor size per mouse for the empty, UVDE-TAT, UVDE-NLS-TAT, and cv-pdg-NLS liposome-treated groups were 12.2 mm, 2.9 mm, 2.1 mm, and 4.2 mm, respectively.”
    Quote in the paperSubstantial claim
  • Findingown data

    Histologic analyses of the tumors that formed were indistinguishable among the 4 groups.

    “Even though the total tumor burden at 33 weeks and the time-to-death analyses revealed significant differences, histologic analyses of the tumors that formed were indistinguishable among the 4 groups.”
    Quote in the paperNot a substantial claim
  • Findingown data

    UVDE-NLS-TAT mice had 75% less risk (95% CI: 93% to 19% less) of being euthanized than control mice during the treatment period.

    “Thus, UVDE-NLS-TAT mice had 75% less (95% CI: 93% to 19% less) risk of being euthanized than control mice during the treatment period.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Proportional risks of euthanasia across all time points.
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    At 33 weeks, total tumor burden averages compared to empty liposome controls were statistically significant for UVDE-TAT (p = 0.041) and UVDE-NLS-TAT (p = 0.045), but not for cv-pdg-NLS (p = 0.541).

    “These tumor burden averages, when compared to empty liposome controls, were statistically significant for UVDE-TAT (p = 0.041) and UVDE-NLS-TAT (p = 0.045), but not for cv-pdg-NLS (p = 0.541).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All examined tumors were asymmetric and poorly circumscribed epithelial neoplasms, characterized by irregular aggregates extending into the superficial to deep dermis or into subcutis and underlying muscle, with features highly characteristic of SCCs.

    “All examined tumors were asymmetric and poorly circumscribed epithelial neoplasms, characterized by irregular aggregates extending into the superficial to deep dermis or, in some cases, into the subcutis and underlying muscle (Fig. 6).”
    • Also stated in: § UVB-induced Carcinogenesis · boosted
      “These features are highly characteristic of SCCs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 33 weeks of UVB irradiation, mean total tumor size per mouse was ~25 mm in the control group, ~12 mm in both UVDE treatment groups, and 18.3 mm in the cv-pdg-NLS group.

    “The mean total tumor size per mouse was ~25 mm in the control group, ~12 mm in both the UVDE treatment groups, and 18.3 mm in the cv-pdg-NLS group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Hazard ratios for euthanasia relative to control were 0.35 (95% CI: 0.11, 1.05) for UVDE-TAT, 0.25 (95% CI: 0.07, 0.81) for UVDE-NLS-TAT, and 0.56 (95% CI: 0.21, 1.55) for cv-pdg-NLS.

    “Assuming proportional risks of euthanasia across all time points, estimated hazard (risk) ratios involving the control group were 0.35 (95% CI: 0.11, 1.05) for UVDE-TAT, 0.25 (95% CI: 0.07, 0.81) for UVDE-NLS-TAT, and 0.56 (95% CI: 0.21, 1.55) for cv-pdg-NLS.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Proportional risks of euthanasia across all time points.

  • May combine two claims.

    Findingown data

    Kaplan-Meier survival curves of control vs UVDE-TAT and UVDE-NLS-TAT mice revealed survival advantages in these active treatment groups, with log-rank test p values of 0.135 and 0.037, respectively.

    “Without having to assume a constant risk ratio across time, analyses of Kaplan-Meier survival curves of control vs UVDE-TAT and UVDE-NLS-TAT mice revealed survival advantages in these active treatment groups, with log-rank test p values of 0.135 and 0.037, respectively (Fig. 5a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 23 weeks, the empty-liposome treated group had 28 tumors with aggregate total tumor size 122 mm; UVDE-TAT, UVDE-NLS-TAT, and cv-pdg-NLS groups had 18, 15, and 19 tumors and aggregate tumor sizes 29 mm, 21 mm, and 42 mm, respectively.

    “The empty-liposome treated group had a total of 28 tumors with an aggregate total tumor size of 122 mm at 23 weeks. In contrast, the UVDE-TAT, UVDE-NLS-TAT, and cv-pdg-NLS groups had 18, 15, and 19 tumors, respectively, and aggregated tumor sizes of 29 mm, 21 mm, and 42 mm, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 23 weeks, mean differences in total tumor size for UVDE-TAT, UVDE-NLS-TAT, and cv-pdg-NLS relative to control were not statistically significant (p = 0.092, 0.058, and 0.179, respectively).

    “The mean differences in total tumor size for UVDE-TAT, UVDE-NLS-TAT, and cv-pdg-NLS relative to the control group were not statistically significant (p = 0.092, 0.058, and 0.179, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    T4-pdg can initiate repair following UV damage of XP cells and increase survival in XP cells.

    “Collectively, several studies have shown that T4-pdg could not only initiate repair following UV damage of XP cells13, but also increase survival in XP cells14.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Tanaka, K., Sekiguchi, M. & Okada, Y. Restoration of ultraviolet-induced unscheduled DNA synthesis of xeroderma pigmentosum cells by the concomitant treatment with bacteriophage T4 endonuclease V and HVJ (Sendai virus). Proc Natl Acad Sci USA 72, 4071–4075 (1975). source

      Not checked in the free run.

    • cites [14] Francis, M. A., Bagga, P., Athwal, R. & Rainbow, A. J. Partial complementation of the DNA repair defects in cells from xeroderma pigmentosum groups A, C, D and F but not G by the denV gene from bacteriophage T4. Photochem Photobiol 72, 365–373 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UVDE from Schizosaccharomyces pombe has broad substrate specificity including both CPDs and 6-4 PPs and initiates the nucleotide incision repair (NIR) pathway.

    “However, the UV endonuclease (UVDE) from Schizosaccharomyces pombe has a very broad substrate specificity which includes both CPDs and 6–4 PPs and is known to initiate the nucleotide incision repair (NIR) pathway18,19.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Avery, A. M. et al. Substrate specificity of ultraviolet DNA endonuclease (UVDE/Uve1p) from Schizosaccharomyces pombe. Nucleic Acids Res 27, 2256–2264 (1999). source

      Not checked in the free run.

    • cites [19] Kaur, B. & Doetsch, P. W. Ultraviolet damage endonuclease (Uve1p): a structure and strand-specific DNA endonuclease. Biochemistry 39, 5788–5796 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In UV-irradiated XPA cells expressing Neurospora crassa UVDE, single-strand breaks were introduced immediately following irradiation and were efficiently repaired, resulting in enhanced survival approaching that of wild-type cells.

    “Further, in UV-irradiated XPA cells expressing the Neurospora crassa UVDE, single-strand breaks were introduced immediately following irradiation and were efficiently repaired, resulting in enhanced survival approaching that of wild-type cells31,32.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Asagoshi, K. et al. DNA polymerase beta-dependent long patch base excision repair in living cells. DNA Repair (Amst) 9, 109–119, https://doi.org/10.1016/j.dnarep.2009.11.002 (2010). source

      Not checked in the free run.

    • cites [32] Okano, S., Kanno, S., Nakajima, S. & Yasui, A. Cellular responses and repair of single-strand breaks introduced by UV damage endonuclease in mammalian cells. J Biol Chem 275, 32635–32641, https://doi.org/10.1074/jbc.M004085200 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exposure to UV irradiation in sunlight causes NMSC by inducing DNA damage that, if replicated, leads to mutations in genes such as KRAS or TP53.

    “Exposure to UV irradiation in sunlight causes NMSC by inducing DNA damage that if replicated, leads to mutations in genes such as KRAS or TP537”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Sarasin, A. The molecular pathways of ultraviolet-induced carcinogenesis. Mutat Res 428, 5–10 (1999). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CPDs account for at least 80% of UVB-induced mutagenesis but contribute only modestly to cytotoxicity in a mammalian cell model.

    “CPDs account for at least 80% of UVB-induced mutagenesis but contribute only modestly to cytotoxicity in a mammalian cell model; however, 6–4 PPs are minimally mutagenic but highly cytotoxic9,10.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Lo, H. L. et al. Differential biologic effects of CPD and 6-4PP UV-induced DNA damage on the induction of apoptosis and cell-cycle arrest. BMC Cancer 5, 135, https://doi.org/10.1186/1471-2407-5-135 (2005). source

      Not checked in the free run.

    • cites [10] You, Y. H. et al. Cyclobutane pyrimidine dimers are responsible for the vast majority of mutations induced by UVB irradiation in mammalian cells. J Biol Chem 276, 44688–44694, https://doi.org/10.1074/jbc.M107696200 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    6-4 PPs are minimally mutagenic but highly cytotoxic.

    “CPDs account for at least 80% of UVB-induced mutagenesis but contribute only modestly to cytotoxicity in a mammalian cell model; however, 6–4 PPs are minimally mutagenic but highly cytotoxic9,10.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Lo, H. L. et al. Differential biologic effects of CPD and 6-4PP UV-induced DNA damage on the induction of apoptosis and cell-cycle arrest. BMC Cancer 5, 135, https://doi.org/10.1186/1471-2407-5-135 (2005). source

      Not checked in the free run.

    • cites [10] You, Y. H. et al. Cyclobutane pyrimidine dimers are responsible for the vast majority of mutations induced by UVB irradiation in mammalian cells. J Biol Chem 276, 44688–44694, https://doi.org/10.1074/jbc.M107696200 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Delivery of T4-pdg in mouse models increased the rate of CPD removal, reduced the frequency of SCC, and minimized UVB-induced immune suppression.

    “Delivery of T4-pdg in mouse models increased the rate of CPD removal, reduced the frequency of SCC, and minimized UVB-induced immune suppression.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Yarosh, D. et al. Localization of liposomes containing a DNA repair enzyme in murine skin. J Invest Dermatol 103, 461–468 (1994). source

      Not checked in the free run.

    • cites [16] Yarosh, D. et al. Enzyme therapy of xeroderma pigmentosum: safety and efficacy testing of T4N5 liposome lotion containing a prokaryotic DNA repair enzyme. Photodermatol Photoimmunol Photomed 12, 122–130 (1996). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UVDE initiates repair at both dipyrimidine photoproducts by incision immediately 5′ to the damage, followed by long-patch BER in conjunction with Rad27/Fen1, XRCC1, PARP1, and DNA polymerase.

    “UVDE initiates repair at both dipyrimidine photoproducts by incision immediately 5′ to the damage18,28,29, followed by long-patch BER in conjunction with Rad27/Fen1, XRCC1, PARP1, and DNA polymerase30–33.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Avery, A. M. et al. Substrate specificity of ultraviolet DNA endonuclease (UVDE/Uve1p) from Schizosaccharomyces pombe. Nucleic Acids Res 27, 2256–2264 (1999). source

      Not checked in the free run.

    • cites [28] Bowman, K. K. et al. A new ATP-independent DNA endonuclease from Schizosaccharomyces pombe that recognizes cyclobutane pyrimidine dimers and 6-4 photoproducts. Nucleic Acids Res 22, 3026–3032 (1994). source

      Not checked in the free run.

    • cites [29] Takao, M., Yonemasu, R., Yamamoto, K. & Yasui, A. Characterization of a UV endonuclease gene from the fission yeast Schizosaccharomyces pombe and its bacterial homolog. Nucleic Acids Res 24, 1267–1271 (1996). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In clinical trials with XP patients using topically delivered T4-pdg, new pre-cancerous lesions (actinic keratosis) were reduced by 68% and new cases of BCC were reduced by 30% compared to placebo lotion.

    “Results of clinical trials with XP patients using topically delivered T4-pdg showed that new pre-cancerous lesions (actinic keratosis) were reduced by 68% and new cases of BCC were reduced by 30% compared to patients treated with placebo lotion17.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Yarosh, D. et al. Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group. Lancet 357, 926–929 (2001). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    There were no missing values for total tumor size comparisons at either of the two time points of interest (23 weeks and 33 weeks) since a mouse's last measured value was carried over if it had been euthanized prior to the time point.

    “There were no missing values for total tumor size comparisons at either of the two time points of interest (23 weeks and 33 weeks) since a mouse’s last measured value was carried over if it had been euthanized prior to the time point.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Following UVB irradiation, UVDE-initiated repair results in rapid, long-patch processes, improving survival in DNA repair-deficient cells.

    “Collectively, these data present consistent evidence that following UVB irradiation, UVDE-initiated repair results in rapid, long-patch processes, improving survival in DNA repair-deficient cells.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] Asagoshi, K. et al. DNA polymerase beta-dependent long patch base excision repair in living cells. DNA Repair (Amst) 9, 109–119, https://doi.org/10.1016/j.dnarep.2009.11.002 (2010). source

      Not checked in the free run.

    • cites [32] Okano, S., Kanno, S., Nakajima, S. & Yasui, A. Cellular responses and repair of single-strand breaks introduced by UV damage endonuclease in mammalian cells. J Biol Chem 275, 32635–32641, https://doi.org/10.1074/jbc.M004085200 (2000). source

      Not checked in the free run.

    • cites [34] Yasuhira, S. & Yasui, A. Alternative excision repair pathway of UV-damaged DNA in Schizosaccharomyces pombe operates both in nucleus and in mitochondria. J Biol Chem 275, 11824–11828 (2000). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    A UVB dose escalation strategy was used for the initial irradiations to prevent significant skin irritation and burning.

    “To prevent significant skin irritation and burning, a UVB dose escalation strategy was used for the initial irradiations.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A total of 50 SKH1 hairless mice were randomly divided into 4 treatment groups (10 mice each).

    “A total of 50 SKH1 hairless mice were randomly divided into 4 treatment groups (10 mice each), while an additional 10 mice were held with no treatments for observation of spontaneous tumor formation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The potential deleterious effects of unrepaired DNA damage have the capacity to increase genomic instability and reduce immune surveillance, both of which increase the risk of cellular transformation.

    “Thus, the potential deleterious effects of unrepaired DNA damage have the capacity to increase genomic instability and reduce immune surveillance, both of which increase the risk of cellular transformation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Although the sample distributions of total tumor size were often positively skewed, this outcome was analyzed using a one-way ANOVA because this method is known to be robust to deviations from the normality assumption.

    “Although the sample distributions of total tumor size were often positively skewed, this outcome was nonetheless analyzed using a one-way ANOVA as this method is known to be robust to deviations from the normality assumption.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Discrepancies in the variance of total tumor size between treatment groups discouraged the use of a nonparametric method that assumes the distributions have equal spread.

    “Moreover, discrepancies in the variance of total tumor size between treatment groups discouraged the use of a nonparametric method that assumes the distributions have equal spread.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    At each of the two time points of interest, the significance of total tumor burden differences between treatment groups was quantified with Tukey-adjusted pairwise p-values from the corresponding ANOVA model.

    “At each of the two time points of interest, the significance of total tumor burden differences between treatment groups was quantified with Tukey-adjusted pairwise p-values from the corresponding ANOVA model.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Reported log-rank p-values for pairwise comparisons between treatment groups were adjusted for multiplicity using the Tukey method.

    “Reported log-rank p-values for pairwise comparisons between treatment groups were adjusted for multiplicity using the Tukey method41.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Kramer, C. Y. Extension of Multiple Range Tests to Group Means with Unequal Numbers of Replications. Biometrics 12, 307–310 (1956). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All liposomes were formulated with hydrogel to yield a final concentration of 0.75%, which allowed uniform distribution and absorbance into the mouse skin.

    “All liposomes were formulated with hydrogel to yield a final concentration of 0.75%, which allowed uniform distribution and absorbance into the mouse skin.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The sequences of the complete genes were confirmed prior to expression studies.

    “The sequences of the complete genes were confirmed prior to expression studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The purity of the DNA repair enzymes was assessed by Coomassie staining following electrophoretic separation.

    “The purity of the DNA repair enzymes was assessed by Coomassie staining of proteins following electrophoretic separation through a denaturing 15% polyacrylamide gel.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The temporal hierarchy of NER of UV-induced dipyrimidine photoproducts in mammalian cells is characterized by rapid recognition and excision of 6-4 PPs and preferential repair of CPDs in actively transcribed genes.

    “The temporal hierarchy of NER of UV-induced dipyrimidine photoproducts in mammalian cells is characterized by not only rapid recognition and excision of 6–4 PPs (which are preferentially formed in open chromatin regions), but also preferential repair of CPDs in actively transcribed genes22–24.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Spivak, G. Transcription-coupled repair: an update. Arch Toxicol 90, 2583–2594, https://doi.org/10.1007/s00204-016-1820-x (2016). source

      Not checked in the free run.

    • cites [23] Spivak, G. & Ganesan, A. K. The complex choreography of transcription-coupled repair. DNA Repair (Amst) 19, 64–70, https://doi.org/10.1016/j.dnarep.2014.03.025 (2014). source

      Not checked in the free run.

    • cites [24] Spivak, G. & Hanawalt, P. C. Photosensitive human syndromes. Mutat Res 776, 24–30, https://doi.org/10.1016/j.mrfmmm.2014.11.003 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Photographs of the Coomassie-stained gels were not manipulated or spliced, but represent a single stained gel.

    “Photographs of the Coomassie-stained gels were not manipulated or spliced, but represent a single stained gel.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The sequences of all gene constructs were verified prior to expression studies.

    “The sequences of all gene constructs were verified prior to expression studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Study design and conductnone given

    The Cox model assumption that the risks of death are proportional over the study period for the groups being compared was checked and found to be justifiable.

    “The Cox model assumption that the risks of death are proportional over the study period for the groups being compared was checked and found to be justifiable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Following 9 UVB exposures (total 2.0 kJ/m2) over 3 weeks, the dorsal skin showed mild redness, slight loss in elasticity, and thickening, without any evidence of sunburn.

    “As anticipated, following 9 UVB exposures (a total exposure of 2.0 kJ/m2) over the course of 3 weeks, the dorsal skin showed evidence of mild redness, slight loss in elasticity, and thickening, without any evidence of sunburn.”
    Quote in the paperNot a substantial claim
33 of 33

  • The paper relies on this without support.

    Previous efforts to develop experimental strategies to enhance the repair capacity of basal keratinocytes have been limited.

    “Since previous efforts to develop experimental strategies to enhance the repair capacity of basal keratinocytes have been limited”

  • The paper relies on this without support.

    Humans possess only one mechanism, the nucleotide excision repair (NER) pathway, for repairing dipyrimidine DNA lesions.

    “Humans possess only one mechanism, the nucleotide excision repair (NER) pathway, for repairing dipyrimidine DNA lesions.”

  • The paper relies on this without support.

    Humans have all enzymes necessary for completing BER, but lack a pyrimidine dimer-specific DNA glycosylase (pdg) to recognize CPDs and initiate the cascade.

    “Humans have all of the enzymes necessary for completing BER, but lack an enzyme, a pyrimidine dimer-specific DNA glycosylase (pdg) to recognize CPDs and initiate the cascade.”

  • The authors state this as an assumption.

    Proportional risks of euthanasia across all time points.

    “Assuming proportional risks of euthanasia across all time points”

  • The paper relies on this without support.

    Two common types of UVB-induced DNA damage are cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4 PPs).

    “Two common types of UVB-induced DNA damage are cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4 PPs).”

  • The paper relies on this without support.

    Mammalian cells exclusively use NER to initiate the repair of dipyrimidine photoproducts.

    “Since mammalian cells exclusively use NER to initiate the repair of dipyrimidine photoproducts”

  • The paper relies on this without support.

    The truncated form of UVDE retains full catalytic activity.

    “To increase its solubility while retaining full catalytic activity, previous studies have characterized a soluble form of UVDE in which the N-terminal 228 amino acids were deleted (Δ228-UVDE).”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Weekly UVB dose conflicts with the 23-week cumulative dose

    Major

    After the first three weeks, 20 weeks at approximately 22 kJ/m2/week would add approximately 440 kJ/m2. That already exceeds the stated 311 kJ/m2 cumulative exposure at week 23.

  • Abstract reverses the reported survival effect

    Major

    The abstract says UVDE-NLS-TAT significantly reduced time to death, whereas the Results report a significant survival advantage for that group. A survival advantage means a longer, not shorter, time to death.

  • The purported same NLS has different stated lengths

    Minor

    The UVDE NLS is specified as seven amino acids, but the cv-pdg construct is said to contain the same 10-amino-acid NLS.

  • Encoded cv-pdg NLS does not match its stated amino-acid sequence

    Minor

    The eighth codon in the given DNA sequence is AAG, which encodes lysine (K), not the glycine (G) at position eight of the stated amino-acid sequence. The DNA sequence instead encodes PGPKKKRKRL.

4 of 4

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Sha, Y., Vartanian, V., Owen, N., Mengden Koon, S. J., Calkins, M. J., Thompson, C. S., Mirafzali, Z., Mir, S., Goldsmith, L. E., He, H., Luo, C., Brown, S. M., Doetsch, P. W., Kaempf, A., Lim, J. Y., McCullough, A. K., & Lloyd, R. S.
Affiliations
  • Oregon Health & Science University (US)
  • National Institutes of Health (US)
Corresponding author
Lloyd, R. Stephen
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-01-15
Volume
8
Issue
1
Pages
705-705
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-17940-8
PMC
PMC5768739
OpenAlex
W2782804296
Cited by
12
References
42
Citations by year
2026: 1 · 2024: 1 · 2023: 1 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 2
FWCI
0.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institutes of Health (NIH-R01)
  • National Cancer Institute (T32CA106195)
  • National Institute of Environmental Health Sciences (R42ES021623, R01ES004091)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
  • Health Sciences › Medicine › Dermatology › Skin Protection and Aging
Keywords
DNA repair, UV endonuclease, Schizosaccharomyces pombe, cell-penetrating peptides, nuclear localization signal, topical enzyme therapy, squamous cell carcinoma, basal cell carcinoma, melanoma, keratinocytes, genomic instability
MeSH terms
Animals, DNA Repair, Mice, Hairless, Recombinant Proteins, Skin Neoplasms, Ultraviolet Rays, DNA Repair Enzymes, Carcinogenesis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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