DNA polymerase η mutational signatures are found in a variety of different types of cancer
Open accessAbstract
DNA polymerase (pol) η is a specialized error-prone polymerase with at least two quite different and contrasting cellular roles: to mitigate the genetic consequences of solar UV irradiation, and promote somatic hypermutation in the variable regions of immunoglobulin genes. Misregulation and mistargeting of pol η can compromise genome integrity. We explored whether the mutational signature of pol η could be found in datasets of human somatic mutations derived from normal and cancer cells. A substantial excess of single and tandem somatic mutations within known pol η mutable motifs was noted in skin cancer as well as in many other types of human cancer, suggesting that somatic mutations in A:T bases generated by DNA polymerase η are a common feature of tumorigenesis. Another peculiarity of pol ηmutational signatures, mutations in YCG motifs, led us to speculate that error-prone DNA synthesis opposite methylated CpG dinucleotides by misregulated pol η in tumors might constitute an additional mechanism of cytosine demethylation in this hypermutable dinucleotide.
Verified 2026-10-06 · 1 reference not checked yet
AI snapshot
Written from the paper’s full text.
TL;DR
This study searched human somatic mutation datasets for the mutational footprint of DNA polymerase η and found enrichment of its mutable motifs in skin melanoma and many other cancers, but not in normal skin or several tumor types. The authors also observed a negative correlation between AID- and pol η-associated motif excess and linked POLH expression patterns to some tumor cohorts.
Key findings
- In normal skin, mutations were enriched 1.2-fold in TC/GA and CT/AG motifs (P < 10⁻¹⁰), while WA/TW showed no significant excess. Skin cancer overall showed excesses for both TC/GA–CT/AG (1.09, P < 10⁻¹⁰) and WA/TW (1.37, P < 10⁻¹⁰); skin cutaneous melanoma showed stronger excesses (1.47 and 1.42, both P < 10⁻¹⁰), whereas skin adenocarcinoma showed none.
- Among non-skin cancers, single mutations in WA/TW were significantly enriched in 11 of 14 solid tumor types, including skin (1.38), rectum (1.22), stomach (1.17), prostate (1.15), kidney (1.14), pancreas (1.13), cervix (1.11), bladder (1.1), colon (1.08), breast (1.06), and ovary (1.03, P = 0.0006). No significant excess was found for merged blood cancers, acute myeloid leukemia, liver, lung, or uterus; CLL (1.22, P = 0.00009) and GCB lymphomas (1.44, P = 0.00003) were significant blood-cancer subtypes.
- Tandem mutations in WA/TW were significantly enriched in 3 of 8 cancer types: lung (2.6, P = 5.3 × 10⁻⁶), ovary (5.65, P = 4.7 × 10⁻⁶), and skin (1.47, P = 6 × 10⁻⁸); across all somatic mutations the excess was 1.83 (P < 10⁻¹⁰). Lung squamous cell carcinoma showed a 1.3-fold excess (P = 0.0005), while lung adenocarcinoma did not.
- AID- and pol η-associated motif excesses were negatively correlated (R = −0.44, P = 0.044, one-tailed). POLH expression was high in skin cutaneous melanoma and lymphoid neoplasm diffuse large B-cell lymphoma, and reduced in colorectal and uterine cancer cohorts.
Methods
- Somatic mutation datasets came from normal skin, various normal tissues, and ICGC/TCGA cancer genome projects via the Sanger COSMIC Whole Genome Project v75. For each substitution, a 120-bp sequence centered on the mutation was extracted, and the frequency of pol η motifs at mutated sites was compared with motif frequency in the surrounding neighborhood using the Fm/Fs ratio and Fisher’s exact test.
- A power analysis for normal tissues used 1,000 resampling iterations with sample sizes matched to the normal-tissue mutation set (552 mutations). POLH expression was analyzed from TCGA RNA-Seq data using normalized RSEM values retrieved through FireBrowse.
Limitations
- The paper states that the WA/TW motif is short and less informative than AID/APOBEC motifs; that signature decomposition is heuristic and a signature cannot be assumed to reflect only one molecular mechanism; that the proposed YCG demethylation role for pol η requires experimental validation; and that the AID–pol η negative correlation is only marginally significant. It also notes that normal-tissue datasets are limited, though its power analysis suggested the negative findings likely reflect biology.
- Evident from the text: the work is correlational and does not directly demonstrate pol η activity in tumors; cancer mutation spectra may be influenced by exogenous mutagens such as smoking or UV, by differing subtype representation, and by hotspot events such as BCL2 translocation, which the authors show can skew exome-wide motif analyses.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
0 of 34 cited sources checked · 0 supported · 0 flagged
- Findingown data
In lung adenocarcinoma, no significant association between mutations and the WA/TW context was found.
“No significant association between mutations and the WA/TW context was found in lung adenocarcinoma, whereas a significant excess (1.3, P = 0.0005) of somatic mutations in the WA/TW context was found for lung squamous cell carcinoma”
Quote in the paperSubstantial claim - Findingown data
POLH gene expression is highly variable across TCGA cohorts.
“The observed high variability in POLH gene expression suggests that the gene is highly expressed only in a subset of TCGA tumor cohorts (Supplementary Figure 1) which is consistent with previous studies 44 .”
Quote in the paperNot a substantial claim - Findingcitation
Colorectal and uterine cancer subsets (COAD, UCEC), previously reported to have no association with pol η activity, show reduced POLH expression.
“Notably, subsets of colorectal and uterine cancer (COAD, UCEC), which have been previously reported to have no association with polymerase pol h activity, exhibit reduced POLH gene expression 45,46 .”
Quote in the paperNot a substantial claim0 of 2 sources checked - Findingown data
In normal skin samples, single mutations in TC/GA and CT/AG dinucleotides showed a 1.2-fold excess.
“A 1.2-fold excess of mutations (defined as described in Materials and Methods) in TC/GA and CT/AG dinucleotides was detected (Table 1).”
Quote in the paperSubstantial claim - Findingown data
In follicular lymphoma, 24% of mutated 5'UTR WA/TW motifs occurred within the BCL2 gene (19 of 28 mutations at A:T bases).
“Specifically, a detailed analysis of pol h mutability suggested that a substantial proportion (24%) of mutated 5'UTR WA/TW motifs occurred within the BCL2 gene (19 out of 28 mutations at A: T bases).”
Quote in the paperSubstantial claim
- Findingown data
No significant excess of somatic mutations in WA/TW motifs was found when all blood cancer types were merged.
“We did not find any significant excess of somatic mutations in WA/TW motifs in all types of blood cancer merged together (Table 2).”
Quote in the paperSubstantial claim - Findingown data
Significant excess of somatic mutations in WA/TW motifs was found in 11 of 14 solid tumors from various tissue types.
“We found a significant excess of somatic mutations in WA/ TW motifs in 11 out of 14 solid tumors from various tissue types (Table 2).”
Quote in the paperSubstantial claim - Findingown data
After removing BCL2 5'UTR mutations, the correlation between pol η WA/TW motifs and mutations in follicular lymphoma became insignificant (P = 0.11; 60 of 116 mutations at A:T bases).
“After we removed mutations that were identified within the BCL2 5'UTR region (near the translocation breakpoint), the correlation became insignificant (P-value = 0.11, 60 mutations in WA/TW motifs out of 116 mutations at A:T bases) 27 .”
Quote in the paperSubstantial claim - Findingown data
In normal skin samples, mutations were not associated with the WA/TW motif.
“By contrast, there was no association between mutations and the WA/TW motif, associated with predominant errors of pol h when copying undamaged DNA 23,29 , indicating that pol h is unlikely to be involved in mutagenesis at undamaged DNA sites in normal skin cells (Table 1).”
Quote in the paperSubstantial claim - Findingown data
Significant excess of somatic mutations in WA/TW motifs was found in chronic lymphocytic leukemia and GCB lymphomas.
“However, we did find such an excess in chronic lymphocytic leukemia (CLL) and GCB lymphomas (subtypes of blood cancer) (Table 2), whereas no significant excess was found for acute myeloid leukemia (AML) (Table 2).”
Quote in the paperSubstantial claim - Findingreasoning
In skin adenocarcinoma, no excess of somatic mutations in the mutable motifs was found.
“However, no such excess was found for skin adenocarcinoma (Table 1), consistent with the fact that adenocarcinoma initiates in the glandular cells that are located deep inside or even under skin tissues, where no elevated frequency of UV photoproducts and mutations caused by DNA pol h in pyrimidine dinucleotides is to be expected.”
Quote in the paperSubstantial claim - Findingown data
In lung cancer, a significant excess of tandem mutations in WA/TW appears to contradict the absence of association between single mutations and WA/TW.
“A significant excess of tandem mutations in lung cancer (Table 3) appears to contradict the absence of any association between single somatic mutations and the WA/TW context (Table 2).”
Quote in the paperNot a substantial claim - Findingown data
POLH appears highly expressed in skin cutaneous melanoma (SKCM).
“Specifically, POLH seems to be highly expressed in skin cutaneous melanoma (SKCM), consistent with a substantial and significant excess of pol h mutational signatures in this cancer type (Table 1).”
Quote in the paperNot a substantial claim - Findingown data
Significant excess of tandem mutations in the WA/TW context was found in 3 of 8 cancer types.
“Although tandem mutations occur much less frequently, we nevertheless found a significant excess of tandem mutations in the WA/TW context in 3 out of 8 cancer types (Table 3).”
Quote in the paperSubstantial claim - Findingown data
A negative correlation (R = −0.44, P = 0.044, one-tailed) was found between AID and pol η mutable motif mutation excesses across cancer types.
“We found a negative correlation (R = ¡0.44) between these two variables (Figure 2) which suggested that AID and pol h are even decoupled in cancer-related mutagenesis (though the observed negative correlation is marginally significant, P = 0.044, one-tailed test).”
Quote in the paperSubstantial claim - Findingown data
In various normal tissues, no significant excess of WA/TW mutable motifs was found.
“As a control, we examined the context of somatic mutations in various normal tissues 43 and did not find any significant excess of WA/TW mutable motifs (Supplemental Table 1).”
Quote in the paperSubstantial claim - Findingown data
No significant excess of somatic mutations in WA/TW motifs was found in acute myeloid leukemia.
“However, we did find such an excess in chronic lymphocytic leukemia (CLL) and GCB lymphomas (subtypes of blood cancer) (Table 2), whereas no significant excess was found for acute myeloid leukemia (AML) (Table 2).”
Quote in the paperSubstantial claim - Findingown data
In lung squamous cell carcinoma, a significant 1.3-fold excess (P = 0.0005) of somatic mutations in the WA/TW context was found.
“No significant association between mutations and the WA/TW context was found in lung adenocarcinoma, whereas a significant excess (1.3, P = 0.0005) of somatic mutations in the WA/TW context was found for lung squamous cell carcinoma”
Quote in the paperSubstantial claim - Findingown data
A negative correlation was observed between the excess of somatic mutations associated with AID and pol η mutable motifs in various types of cancer (Figure 2).
“The evidence for that comes from the observed negative correlation between the excess of somatic mutations associated with AID and pol h mutable motifs in various types of cancer (Figure 2).”
Quote in the paperSubstantial claim - Findingreasoning
No significant excess of mutations in DNA polymerase η motifs was found for acute myeloid leukemia (Table 2).
“no significant excess of mutation in pol h motifs was found for acute myeloid leukemia (Table 2)”
Quote in the paperSubstantial claim - Findingown data
Reduced POLH expression was observed in tumor cohorts where no pol η-specific mutation signatures were detected.
“Conversely, a reduced level of POLH expression was observed in tumor cohorts where no pol h-specific mutation signatures were detected.”
Quote in the paperNot a substantial claim - Findingown data
The authors detected overlaps between DNA polymerase η mutational signatures and somatic mutations in various cancers.
“We detected overlaps between pol h signatures with somatic mutations in various cancers.”
Quote in the paperSubstantial claim - Findingown data
Elevated POLH expression was observed in tumor cohorts where pol η-specific mutation signatures were detected.
“Importantly, an elevated level of POLH expression was observed in tumor cohorts where pol h-specific mutation signatures were detected.”
Quote in the paperSubstantial claim - Interpretationown data
AID and pol η are decoupled in cancer-related mutagenesis.
“We found a negative correlation (R = ¡0.44) between these two variables (Figure 2) which suggested that AID and pol h are even decoupled in cancer-related mutagenesis (though the observed negative correlation is marginally significant, P = 0.044, one-tailed test).”
Quote in the paperSubstantial claim - Interpretationown data
pol η may be mutagenic only in some types of blood cancer.
“This suggests that pol h may be mutagenic only in some types of blood cancer, consistent with the results of previous studies 39 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] source
Not checked in the free run.
- Interpretationown data
pol η is unlikely to be involved in mutagenesis at undamaged DNA sites in normal skin cells.
“By contrast, there was no association between mutations and the WA/TW motif, associated with predominant errors of pol h when copying undamaged DNA 23,29 , indicating that pol h is unlikely to be involved in mutagenesis at undamaged DNA sites in normal skin cells (Table 1).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
POLH is highly expressed only in a subset of TCGA tumor cohorts.
“The observed high variability in POLH gene expression suggests that the gene is highly expressed only in a subset of TCGA tumor cohorts (Supplementary Figure 1) which is consistent with previous studies 44 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] source
Not checked in the free run.
- Premisecitation
Signature 9 is a mutation pattern attributed to pol η recruited to repair AID-damaged DNA during somatic hypermutation in immunoglobulin genes.
“is characterized by a pattern of mutations that has been attributed to pol h (see the Discussion section for details) recruited for the repair of DNA damaged by AID during somatic hypermutation in immunoglobulin genes [28][29][30] .”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
The lack of excess in skin adenocarcinoma is consistent with its origin in glandular cells located deep in or under skin, where UV photoproducts and pol η pyrimidine-dinucleotide mutations are not expected.
“However, no such excess was found for skin adenocarcinoma (Table 1), consistent with the fact that adenocarcinoma initiates in the glandular cells that are located deep inside or even under skin tissues, where no elevated frequency of UV photoproducts and mutations caused by DNA pol h in pyrimidine dinucleotides is to be expected.”
Quote in the paperSubstantial claim - Premisecitation
The pol η mutational signature known as Signature 9 occurs in chronic lymphocytic leukemia and malignant B-cell lymphoma genomes.
“It has also been noted that the 'pol h mutational signature' (Signature 9; http://cancer.sanger.ac.uk/cosmic/sig natures) occurs in chronic lymphocytic leukemia and malignant Bcell lymphoma genomes 6,26,27 .”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationown data
High POLH expression in SKCM is consistent with the substantial excess of pol η mutational signatures in this cancer type.
“Specifically, POLH seems to be highly expressed in skin cutaneous melanoma (SKCM), consistent with a substantial and significant excess of pol h mutational signatures in this cancer type (Table 1).”
Quote in the paperNot a substantial claim - Interpretationown data
The absence of significant excess of WA/TW mutations in normal tissues likely reflects genuine biological properties, based on power analysis.
“The size of these datasets is limited, but a power analysis (see Materials and Methods) suggested that the absence of any significant excess of somatic mutations in WA/TW mutable motifs in normal tissues likely reflects genuine biological properties of these samples.”
Quote in the paperSubstantial claim - Premisecitation
In follicular lymphoma, the pol η WA/TW signature was significant only in 5'UTR regions (P = 0.01).
“Previously, we found a signature of pol h (WA/TW) in follicular lymphoma which was significant only in 5'UTR regions (P-value = 0.01) 36 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] source
Not checked in the free run.
- Interpretationcitation
Some endogenous or exogenous mutational mechanisms may have very similar or identical signatures, so a given signature cannot be attributed solely and exclusively to one molecular mechanism.
“In fact, we can never be sure that a given mutational signature can be attributed solely and exclusively to one molecular mechanismindeed, some endogenous or exogenous mutational mechanisms may have very similar or even identical signatures 27,29 .”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
NPM1 deficiency causes a translesion DNA synthesis defect due to proteasomal degradation of DNA polymerase η.
“NPM1 deficiency causes a TLS defect due to the proteasomal degradation of pol h.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] source
Not checked in the free run.
- Interpretationcitation
The excess of pol η mutable motifs in CLL and GCB lymphomas is consistent with Alexandrov et al.'s detection of Signature 9 in CLL and malignant B-cell lymphoma.
“The excess of pol h mutable motifs in chronic lymphocytic leukemia and GCB lymphomas that we detected in our work is consistent with the studies of Alexandrov et al. 39”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] source
Not checked in the free run.
- Interpretationreasoning
The loss of DNA polymerase η due to NPM1 mutation may explain why no significant excess of mutations in pol η motifs was found in acute myeloid leukemia.
“which may explain why no significant excess of mutation in pol h motifs was found for acute myeloid leukemia (Table 2)”
Quote in the paperSubstantial claim - Premisecitation
The prevalent NPM1 mutation (c+) that leads to NPM1 mislocalization in one-third of AML patients results in a loss of DNA polymerase η.
“The prevalent NPM1 mutation (c+) leading in one-third of AML patients to NPM1 mislocalization results in a loss of pol h”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] source
Not checked in the free run.
- May combine two claims. 10
- The quote only partly states this claim. 2
- Classified as probably not a substantial claim. 6
May combine two claims. The quote only partly states this claim.
Findingown dataIn skin cutaneous melanoma, there was a substantial and significant excess of somatic mutations in both the TC/GA and CT/AG motifs and the WA/TW motif.
“A substantial (and significant) excess of somatic mutations for the both mutable motifs was found for skin cutaneous melanoma (Table 1) where the frequency of UV photoproducts is expected to be high.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDNA polymerase η copies undamaged DNA with lower fidelity than most DNA-directed polymerases, with an average base-substitution error rate of 3.5 × 10−2.
“DNA pol h copies undamaged DNA with a lower fidelity than most DNA-directed polymerases with an average base-substitution error rate of 3.5 £ 10 ¡2 [22][23][24] .”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown datapol η may be involved in mutagenesis in some lung cancer subtypes but not others.
“suggesting that DNA pol h may be involved in mutagenesis in some lung cancer subtypes but not others.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationDNA polymerase η bypasses UV photoproducts at TT tandem bases with high accuracy, inserting AA in over 99% of bypass events and reducing mutagenesis.
“Bypass of UV-induced photoproducts at TT tandem bases by the yeast and human translesion pol h (a member of the Y family of specialized DNA polymerases) is relatively accurate; this polymerase inserts the complementary AA nucleotides into the newly synthesized DNA in more than 99% of bypass events”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGermline mutations in POLH cause the variant form of xeroderma pigmentosum, XPV.
“Germline mutations in the gene (POLH) encoding DNA pol h result in XPV, a variant type of xeroderma pigmentosum 25 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
InterpretationreasoningThe contradiction in lung cancer may result from greater sensitivity of tandem mutation analysis or from differential representation of lung cancer subtypes in single and tandem mutation datasets.
“This may result from greater sensitivity of the tandem mutation analysis or from differential representation of lung cancer subtypes in datasets of single and tandem mutations.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationThe mutable motif of pol η is the short WA/TW sequence, defined in somatic hypermutation and in vitro systems.
“The mutable motif of pol h, the short motif WA/TW (W = A or T) was delineated in the context of somatic hypermutations and in vitro systems 22,23 .”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationSignature 9 is characterized by a pattern widely attributed to pol η, although a higher frequency of T:A > G:C transversions compared to T:A > C:G transitions has not been observed in pol η studies in vitro or in vivo.
“although a higher frequency of T:A > G:C transversions compared to T:A > C:G transitions, has not been observed in studies of pol h either in vitro or in vivo 27,29 .”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims. The quote only partly states this claim.
Study design and conductcitationThe approach of comparing mutable motif frequencies in mutation locations to those in the DNA neighborhood was thoroughly tested and demonstrated high accuracy.
“This approach was thoroughly tested and its high accuracy demonstrated 36 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationPrevious studies point to pol η being an important mutagenic factor in normal skin and cancer cells.
“Thus, all these studies point to pol h being an important mutagenic factor in normal skin and cancer cells.”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Study design and conductnone givenThe observed effect size (Supplementary Table 1) is likely to reflect the biological properties of the samples and is unlikely to result from small sample size, at least for somatic mutations from normal tissues.
“Thus, the observed effect size (Supplementary Table 1) is likely to reflect the biological properties of these samples and is unlikely to result from the small sample size, at least for somatic mutations from normal tissues.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationA recent study extended the potential mutagenic activity of pol η to solid tumors, where somatic mutations produced by pol η are likely associated with other factors including exogenous exposures, UV radiation or alcohol consumption.
“The recent study extended a range of potential mutagenic activity of pol h to solid tumors where somatic mutations produced by pol h are likely to be associated with the other factors, including exogenous exposures, UV radiation or alcohol consumption 31 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationDNA polymerase η is thought to scan a limited length of DNA to mutate nucleotides in a preferred motif.
“pol h is thought to scan a limited length of DNA to mutate nucleotides in a preferred motif 36,54 .”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
InterpretationreasoningThe results indicate that regulation of DNA polymerase η in cancer cells is complex and provide an explanation for why pol η mutational signatures are found only in some cancer types/subtypes.
“These results hint at the complexity of regulation of pol h in cancer cells and provide an explanation of why pol h mutational signatures are found only in some cancer types/subtypes.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
pol η is responsible for inaccurate bypass of dimers in CC, TC and CT dinucleotides.
“If we assume that pol h is responsible for the inaccurate bypass of dimers in CC, TC and CT dinucleotides, one would expect there to be an excess of single mutations in TC and CT dinucleotides”
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?
In MM, SBS9 was strongly linked with Q61H.
“In MM, SBS9, associated with mutations introduced by polymerase η repair of activation-induced deaminase (AID) activity26,31,32, was strongly linked with Q61H”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [31]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
GCB lymphoma mutation excess is overstated
MajorThe reported motif excess is defined as the fraction of mutations divided by the fraction of motifs in surrounding regions. For GCB lymphomas, the printed fractions give about 1.14, not 1.44.
Reported 1.44 · recomputed 1.139535
“| GCB lymphomas | 0.49 | 0.43 | 1.44 | 0.00003 |”
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
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Sorted by citations
DNA Damage: From Threat to Treatment
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“When these genes are mutated, the resulting dysfunctional MMR leads to failure in properly recognizing and resolving errors arising from physiological processes, such as DNA replication, therefore priming malignant outcomes [84] or predisposing to cancer [85].”
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Self-citationDNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers
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Meiotic DNA breaks drive multifaceted mutagenesis in the human germ line
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Diverse roles of RAD18 and Y-family DNA polymerases in tumorigenesis
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DNA damage response signaling: A common link between cancer and cardiovascular diseases
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DNA polymerase eta: A potential pharmacological target for cancer therapy
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“Rogozin et al. (2018) have established POLH mutational signatures in skin and some other cancers.”
BackgroundUnravelling roles of error-prone DNA polymerases in shaping cancer genomes
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“To investigate the role of Pol η in cancer mutagenesis, human somatic mutations derived from normal and cancer cells using data from the International Cancer Genome Consortium (ICGC, [118]) and TCGA [63] were examined for the mutable motif characteristic of Pol η [119].”
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“A putative Pol η signature has been found in several cancers, including melanoma and esophageal cancer [100], both of which are amplified in our analyses (Figure 1B).”
BackgroundSomatic mutation load and spectra: A record of DNA damage and repair in healthy human cells
Saini, N., & Gordenin, D. A. (2018) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22215 · Cited by 24 · see citing works
A high-resolution landscape of mutations in the BCL6 super-enhancer in normal human B cells
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“Our mutation spectrum data suggest that, similar to the immunoglobulin genes, the BCL6 SE locus is a target of AID and Pol η resulting in a high prevalence (>60”
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Wilson, K. A., Fernandes, P. A., Ramos, M. J., & Wetmore, S. D. (2019) · ACS Catalysis · doi:10.1021/acscatal.8b04889 · Cited by 23 · see citing works
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Rogozin, I. B., Roche-Lima, A., Lada, A. G., Belinky, F., Sidorenko, I. A., Glazko, G. V., Babenko, V. N., Cooper, D. N., & Pavlov, Y. I. (2019) · Cancers · doi:10.3390/cancers11020211 · Cited by 19 · see citing works
“These results suggest that there is variability of mutation context specificity across the same tissue, as seen previously [39].”
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Cellular and Molecular Mechanisms of Oxidative DNA Damage and Repair
Ayna, A., Çağlayan, C., & Tayşi, S. (2025) · Medicina · doi:10.3390/medicina61112013 · Cited by 21 · see citing works
“Studies have shown that Pol η is overexpressed in many types of cancer, suggesting that it plays an important role in tumorigenesis [158,159].”
Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis
Peddu, C., Zhang, S., Zhao, H. L., Wong, A., Lee, E. Y. C., Lee, M., & Zhang, Z. (2018) · iScience · doi:10.1016/j.isci.2018.07.009 · Cited by 13 · see citing works
Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis
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Rogozin, I. B., Roche-Lima, A., Tyryshkin, K., Carrasquillo-Carrión, K., Lada, A. G., Poliakov, L. Y., Schwartz, E., Saura, A., Yurchenko, V., Cooper, D. N., et al. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.671866 · Cited by 6 · see citing works
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“34 However, an experiment conducted in human fibroblasts found that the overproduction of Pol η does not increase spontaneous mutations, 35 suggesting that the abundance of Pol η alone is unlikely to be a causative factor for mutations in cancers.”
BackgroundCanonical and Non-Canonical Roles of Human DNA Polymerase η
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“Over-expression of Pol η has consequences for genome stability, for example in memory B cells [172], and in tumours where the Pol η -dependent SBS9 mutation signature can be detected [38,173].”
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“TLS polymerases generate many of the mutational signatures present in cancer cells (Rogozin et al., 2018), and the TLS pathway is pathologically activated in many cancers (Gao et al., 2018, 2016).”
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“Mutational signatures in cancer point toward TLS involvement in its genesis ( 8 , 81 , 82 ).”
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“Reports show that POLH overexpression is linked to mutational signatures in breast and lung cancer (Rogozin et al., 2018), while REV1 upregulation promotes chemotherapy resistance and mutagenesis in lung and colon cancers (Zhu et al., 2022).”
Genome Instability and Somatic Mutagenesis in Autoimmune Diseases
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“Subsequently, a parallel mutational signature deconvolution analysis revealed an enrichment of nTw → N mutations in SSc samples, which is a signature of POLH activity, which encodes the translesion synthesis DNA polymerase Pol η (Pol Eta) [142].”
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- Authors
- Rogozin, I. B., Goncearenco, A., Lada, A. G., De, S., Yurchenko, V., Nudelman, G., Panchenko, A. R., Cooper, D. N., & Pavlov, Y. I.
- Affiliations
- National Institutes of Health (US)
- University of California, Davis (US)
- Rutgers, The State University of New Jersey (US)
- University of Ostrava (CZ)
- Icahn School of Medicine at Mount Sinai (US)
- Cardiff University (GB)
- University of Nebraska Medical Center (US)
- Corresponding author
- Rogozin, Igor B.
- Pavlov, Youri I.
- ORCID
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2018-02-01
- Volume
- 17
- Issue
- 3
- Pages
- 348-355
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC5914734
- OpenAlex
- W2769836470
- Cited by
- 39
- References
- 56
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 4 · 2018: 6
- FWCI
- 1.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- National Institutes of Health
- Boettcher Foundation, American Cancer Society (P30 CA072720)
- NE DHHS LB506 (2017-48)
- Moravskoslezsky kraj research initiative (01211/2016/RRC)
- Fred & Pamela Buffett Cancer Center (P30 CA072720)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- mutational signatures, somatic mutations, error-prone DNA replication, skin cancer, CpG demethylation, genome stability, carcinogenesis
- MeSH terms
- Y-Family DNA Polymerases, Base Sequence, DNA-Directed DNA Polymerase, Humans, Mutation, Neoplasms, Skin, Skin Neoplasms, Gene Expression Regulation, Neoplastic, Exome
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