Unravelling roles of error-prone DNA polymerases in shaping cancer genomes

Vaziri, Cyrus; Rogozin, Igor B.; Gu, Qisheng; Wu, Di; Day, Tovah

doi:10.1038/s41388-021-02032-9

Cited by 22 publications

(26 citation statements)

References 144 publications

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“…Several TLS polymerases including Pol η and Pol κ, are important for preventing accumulation of single strand DNA gaps, and the replication of DNA fragile sites. Owing to their high error-propensity, TLS polymerases are likely to contribute to oncogene-induced mutagenesis (43, 44).…”

Section: Discussionmentioning

confidence: 99%

Signatures of defective DNA repair and replication in early-onset renal cancer patients referred for germline genetic testing

Demidova

Serebriiskii

Vlasenkova

et al. 2022

Preprint

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Early-onset renal cell carcinoma (eoRCC) is typically associated with pathogenic germline variants (PGVs) in RCC familial syndrome genes. However, most eoRCC patients lack PGVs in familial RCC genes and their genetic risk remains undefined. Here, we analyzed biospecimens from 22 eoRCC patients that were seen at our institution for genetic counseling and tested negative for PGVs in RCC familial syndrome genes. We performed whole-exome sequencing (WES) and found enrichment of candidate pathogenic germline variants in DNA repair and replication genes, including multiple DNA polymerases. Induction of DNA damage in peripheral blood monocytes (PBMCs) significantly elevated numbers of γH2AX foci, a marker of double-stranded breaks, in PBMCs from eoRCC patients versus PBMCs from matched cancer-free controls. Knockdown of candidate PGVs in Caki RCC cells increased γH2AX foci. Immortalized patient-derived B cells bearing candidate PGVs in DNA polymerase genes (POLD1, POLH, POLE, POLK) had DNA replication defects compared to control cells. Renal tumors carrying these DNA polymerase variants were microsatellite stable but had a high mutational burden. Direct biochemical analysis of the variant Pol δ and Pol η polymerases revealed defective enzymatic activities. Together, these results suggest that constitutional defects in DNA repair such as DNA replication repair underlie a subset of eoRCC cases. These findings may provide opportunities for use of the DNA repair targeting agents for eoRCC treatment. Screening patient lymphocytes to identify these defects may provide insight into mechanisms of carcinogenesis in a subset of genetically undefined eoRCCs.Significance StatementScreening for DNA repair variation may provide a more comprehensive risk assessment for eoRCC patients. Evaluation of DNA repair defects may also provide insight into the cancer initiation mechanisms for subsets of eoRCCs and lay the foundation for targeting DNA repair vulnerabilities in eoRCC.

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Section: Discussionmentioning

confidence: 99%

Signatures of defective DNA repair and replication in early-onset renal cancer patients referred for germline genetic testing

Demidova

Serebriiskii

Vlasenkova

et al. 2022

Preprint

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“…Therefore, XPV is a malignancy resulting from deployment of alternative, more error-prone genome maintenance mediators when an individual Y-family TLS polymerase (Polη) is absent (Figure 1 ). Such ‘imbalance’ and altered DNA repair pathway choice is a general conceptual framework for explaining mechanisms of genome instability in cancer ( 21 ). A good example of how imbalanced DNA repair pathway choice may lead to genetic change is provided by BRCA1 -deficient ovarian cancers in which HR is defective.…”

Section: Tls Pathway Imbalance Due To Polη-deficiency Causes Skin Cancermentioning

confidence: 99%

Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy

et al. 2023

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DNA damage tolerance and mutagenesis are hallmarks and enabling characteristics of neoplastic cells that drive tumorigenesis and allow cancer cells to resist therapy. The ‘Y-family’ trans-lesion synthesis (TLS) DNA polymerases enable cells to replicate damaged genomes, thereby conferring DNA damage tolerance. Moreover, Y-family DNA polymerases are inherently error-prone and cause mutations. Therefore, TLS DNA polymerases are potential mediators of important tumorigenic phenotypes. The skin cancer-propensity syndrome xeroderma pigmentosum-variant (XPV) results from defects in the Y-family DNA Polymerase Pol eta (Polη) and compensatory deployment of alternative inappropriate DNA polymerases. However, the extent to which dysregulated TLS contributes to the underlying etiology of other human cancers is unclear. Here we consider the broad impact of TLS polymerases on tumorigenesis and cancer therapy. We survey the ways in which TLS DNA polymerases are pathologically altered in cancer. We summarize evidence that TLS polymerases shape cancer genomes, and review studies implicating dysregulated TLS as a driver of carcinogenesis. Because many cancer treatment regimens comprise DNA-damaging agents, pharmacological inhibition of TLS is an attractive strategy for sensitizing tumors to genotoxic therapies. Therefore, we discuss the pharmacological tractability of the TLS pathway and summarize recent progress on development of TLS inhibitors for therapeutic purposes.

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“…В клеткахпредшественницах лимфоцитов такие ДНК-полимеразы действуют на строго определенных участках ДНК, кодирующих иммуноглобулины. Экспрессия генов таких ДНК-полимераз вместе с другими древними генами повышена в раковых клетках [64]. И это способствует прогрессии опухоли, включая генерацию вариантов клеток, среди которых могут быть более устойчивыми к реакциям организма на опухолевый рост и к терапевтическим воздействиям.…”

Section: конвергентная эволюция или рекапитуляция?unclassified

Общие Принципы Взаимоотношений Живых Организмов С Экосистемой И Злокачественных Клеток С Живым Организмом

Голубев¹

2022

Biosfera

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The present review addresses studies based on behavioral similarities between cancer cells in a metazoan organism and unicellular organisms in an ecosystem and between malignant tumors and some primordial colonial forms of life, from which metazoans evolved. Unicellular organisms and their colonies can exist only by compensating for their losses by the proliferation of remaining cells. Therefore, proliferation or readiness to proliferate is a priority for cells. Metazoans evolution was associated with increasing the stringency of the control of this priority. In this perspective, the common set of cancer hallmarks, which emerges in the courses of progression of different cancers, which feature different initial combinations of mutations in oncogenes and antioncogenes and exist under different initial conditions possible in various organs, results not from the convergent evolution but rather from the recapitulation of the evolutionary primordial mode of cell life. The malignant transformation is a manifestation of the disinhibition of a gestalt of traits required for the survival of cell populationin an ecosystem, which is what a tumor host eventually turns to for the tumor. Such ecological attitudes to malignant growth suggest analogies betweenthe therapeutic resistance of cancer with the resistance of pests to pesticides or of bacteria to antibiotics and between metastases and invasive species. An important means used by unicellular organisms to survive in noxious conditions is increasing the rate of mutation to produce different variants, among which some may happen to fit the current situation. This is what occurs upon cancer therapy, which increases the genetic diversity of cancer cells and acts as a factor of the positive selection of cells for resistance to the very same therapy. Because the resulting cell clones compete for body resources, the elimination of the cells that respond to therapy is favorable for the cells that are resistant to it. Therefore, it is unwise to use chemotherapy for tumor elimination. It is more prudent to aim at achieving a balance of cancer cell populations, which makes it possible to turn cancer into a chronic rather than fatal disease. These arguments justify the current efforts to develop regiments of the so-called adaptive therapy for cancer.

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Unravelling roles of error-prone DNA polymerases in shaping cancer genomes

Cited by 22 publications

References 144 publications

Signatures of defective DNA repair and replication in early-onset renal cancer patients referred for germline genetic testing

Signatures of defective DNA repair and replication in early-onset renal cancer patients referred for germline genetic testing

Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy

Общие Принципы Взаимоотношений Живых Организмов С Экосистемой И Злокачественных Клеток С Живым Организмом

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