Predominant role of DNA polymerase eta and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells

Lerner, Letícia Koch; Francisco, Guilherme; Soltys, Daniela T.; Rocha, Clarissa Ribeiro Reily; Quinet, Annabel; Vessoni, Alexandre Teixeira; Castro, Ligia Pereira; David, Taynah Ibrahim Picolo; Bustos, Silvina Odete; Strauss, Bryan E.; Gottifredi, Vanesa; Stary, Anne; Sarasin, Alain; Chammas, Roger; Menck, Carlos Frederico Martins

doi:10.1093/nar/gkw1196

Cited by 44 publications

(45 citation statements)

References 44 publications

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“…Resistance to AZD1775-induced replication stress at a replication fork level likely involves a RAD18-TLS polymerase kappa-dependent tolerance pathway and a RAD51-dependent fork protection pathway (13). We propose that p53 may regulate a choice between these pathways both directly (42,43) and in a transcriptionmediated manner (44).…”

Section: Discussionmentioning

confidence: 92%

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Diab

Kao

Kehrli

et al. 2019

Molecular Cancer Research

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The p53 gene is the most commonly mutated gene in solid tumors, but leveraging p53 status in therapy remains a challenge. Previously, we determined that p53 deficiency sensitizes head and neck cancer cells to AZD1775, a WEE1 kinase inhibitor, and translated our findings into a phase I clinical trial. Here, we investigate how p53 affects cellular responses to AZD1775 at the molecular level. We found that p53 modulates both replication stress and mitotic deregulation triggered by WEE1 inhibition. Without p53, slowing of replication forks due to replication stress is exacerbated. Abnormal, gH2AX-positive mitoses become more common and can proceed with damaged or underreplicated DNA. p53-deficient cells fail to properly recover from WEE1 inhibition and exhibit fewer 53BP1 nuclear bodies despite evidence of unresolved damage. A faulty G 1 -S checkpoint propagates this damage into the next division. Together, these deficiencies can intensify damages in each consecutive cell cycle in the drug. Implications:The data encourage the use of AZD1775 in combination with genotoxic modalities against p53-deficient head and neck squamous cell carcinoma. Results Cell-cycle progression and DNA-damage/replication stress response in WEE1 inhibitor-treated HNSCC cellsPhenotypes elicited by a therapeutically relevant dose of the WEE1 inhibitor AZD1775 were first demonstrated in the TP53 Diab et al.

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Section: Discussionmentioning

confidence: 92%

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Diab

Kao

Kehrli

et al. 2019

Molecular Cancer Research

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“…On top of eliminating cells with damaged DNA by apoptosis or senescence, p53 is also capable of enhancing the processivity of DNA replication forks (6). Other groups reported similar findings, considering various mechanisms of how p53 might enhance DNA replication, e.g., through avoiding topological stress (7), inducing DNA polymerase-eta and translesion synthesis (8), orchestrating fork restart (9), or enhancing the levels of pCDKN1A/ p21 and its association with PCNA (10). In other systems, p53 can also compromise DNA replication through p53-associated exonuclease activity and DNA polymerase-iota (11), and forced CDKN1A/p21 synthesis impairs DNA replication in UV-irradiated cells (12).…”

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confidence: 80%

Chromatin modifiers Mdm2 and RNF2 prevent RNA:DNA hybrids that impair DNA replication

Ina

Wohlberedt

Magerhans

et al. 2018

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

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The p53–Mdm2 system is key to tumor suppression. We have recently reported that p53 as well as Mdm2 are capable of supporting DNA replication fork progression. On the other hand, we found that Mdm2 is a modifier of chromatin, modulating polycomb repressor complex (PRC)-driven histone modifications. Here we show that, similar to Mdm2 knockdown, the depletion of PRC members impairs DNA synthesis, as determined in fiber assays. In particular, the ubiquitin ligase and PRC1 component RNF2/Ring1B is required to support DNA replication, similar to Mdm2. Moreover, the Ring finger domain of Mdm2 is not only essential for its ubiquitin ligase activity, but also for proper DNA replication. Strikingly, Mdm2 overexpression can rescue RNF2 depletion with regard to DNA replication fork progression, and vice versa, strongly suggesting that the two ubiquitin ligases perform overlapping functions in this context. H2A overexpression also rescues fork progression upon depletion of Mdm2 or RNF2, but only when the ubiquitination sites K118/K119 are present. Depleting the H2A deubiquitinating enzyme BAP1 reduces the fork rate, suggesting that both ubiquitination and deubiquitination of H2A are required to support fork progression. The depletion of Mdm2 elicits the accumulation of RNA/DNA hybrids, suggesting R-loop formation as a mechanism of impaired DNA replication. Accordingly, RNase H overexpression or the inhibition of the transcription elongation kinase CDK9 each rescues DNA replication upon depletion of Mdm2 or RNF2. Taken together, our results suggest that chromatin modification by Mdm2 and PRC1 ensures smooth DNA replication through the avoidance of R-loop formation.

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“…It is possible that the perturbed cell metabolism leads to the aberrant regulation of pol h, for example, that what one expects in the completely disorganized environment of cell extracts (where the pol h mutagenesis had beed inferred) 50 , or in in vitro systems 22 , while normal cells are well protected from its action 51 . The error-prone action of misregulated pol h is expected to cause a substantial load of somatic mutations, which may be beneficial for cancer initiation and/or progression, for example, when TP53 is mutated 27,52 . Another potential function of pol h in cancer cells could be the error-free or error-prone bypass of various DNA lesions.…”

Section: Discussionmentioning

confidence: 99%

DNA polymerase η mutational signatures are found in a variety of different types of cancer

et al. 2018

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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.

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Predominant role of DNA polymerase eta and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells

Cited by 44 publications

References 44 publications

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Chromatin modifiers Mdm2 and RNF2 prevent RNA:DNA hybrids that impair DNA replication

DNA polymerase η mutational signatures are found in a variety of different types of cancer

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