Hypertranscription and replication stress in cancer

Bowry, Akhil; Kelly, Richard; Petermann, Eva

doi:10.1016/j.trecan.2021.04.006

Cited by 50 publications

(33 citation statements)

References 142 publications

(234 reference statements)

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“…Here, we developed, tested, and applied an approach to combine atomic protein structures with evolutionary trace (ET) and evolutionary action (EA) computational analyses ( Lichtarge et al, 1996 ; Katsonis and Lichtarge, 2014 ). These analyses efficiently identified and objectively assessed the most impactful germline and somatic variants in helicase–nuclease–RPA complexes, which are vital for resolving transcription and replication stress that are common features of cancer cells ( Gomez-Gonzalez and Aguilera, 2019 ; Ubhi and Brown, 2019 ; Bowry et al, 2021 ). Going beyond sequence conservation, ET considers sequence changes that occur and that are retained through evolution to providing those organisms with a functional advantage.…”

Section: Introductionmentioning

confidence: 99%

Decoding Cancer Variants of Unknown Significance for Helicase–Nuclease–RPA Complexes Orchestrating DNA Repair During Transcription and Replication

Tsutakawa

Bacolla

Katsonis³

et al. 2021

Front. Mol. Biosci.

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All tumors have DNA mutations, and a predictive understanding of those mutations could inform clinical treatments. However, 40% of the mutations are variants of unknown significance (VUS), with the challenge being to objectively predict whether a VUS is pathogenic and supports the tumor or whether it is benign. To objectively decode VUS, we mapped cancer sequence data and evolutionary trace (ET) scores onto crystallography and cryo-electron microscopy structures with variant impacts quantitated by evolutionary action (EA) measures. As tumors depend on helicases and nucleases to deal with transcription/replication stress, we targeted helicase–nuclease–RPA complexes: (1) XPB-XPD (within TFIIH), XPF-ERCC1, XPG, and RPA for transcription and nucleotide excision repair pathways and (2) BLM, EXO5, and RPA plus DNA2 for stalled replication fork restart. As validation, EA scoring predicts severe effects for most disease mutations, but disease mutants with low ET scores not only are likely destabilizing but also disrupt sophisticated allosteric mechanisms. For sites of disease mutations and VUS predicted to be severe, we found strong co-localization to ordered regions. Rare discrepancies highlighted the different survival requirements between disease and tumor mutations, as well as the value of examining proteins within complexes. In a genome-wide analysis of 33 cancer types, we found correlation between the number of mutations in each tumor and which pathways or functional processes in which the mutations occur, revealing different mutagenic routes to tumorigenesis. We also found upregulation of ancient genes including BLM, which supports a non-random and concerted cancer process: reversion to a unicellular, proliferation-uncontrolled, status by breaking multicellular constraints on cell division. Together, these genes and global analyses challenge the binary “driver” and “passenger” mutation paradigm, support a gradient impact as revealed by EA scoring from moderate to severe at a single gene level, and indicate reduced regulation as well as activity. The objective quantitative assessment of VUS scoring and gene overexpression in the context of functional interactions and pathways provides insights for biology, oncology, and precision medicine.

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Section: Introductionmentioning

confidence: 99%

Decoding Cancer Variants of Unknown Significance for Helicase–Nuclease–RPA Complexes Orchestrating DNA Repair During Transcription and Replication

Tsutakawa

Bacolla

Katsonis³

et al. 2021

Front. Mol. Biosci.

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“…We used hydroxyurea to cause replication stress due to a general stalling of replication forks and tested how the inhibition of ATM affects cell fate upon such conditions. Oncogenes like mutated RAS cause DNA replication stress due to increased cell proliferation [74] and loss-of-function mutations in the DNA repair proteins BRCA1, BRCA2, ATM, and PALB2 occur in inherited and sporadic PDAC cells [75]. Mouse models with an expression of an oncogenic mutant of the small G protein RAS [76] and a deletion of ATM in the pancreas mimic human PDAC [77].…”

Section: Discussionmentioning

confidence: 99%

Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion

Nguyen

Dzulko

Murr

et al. 2021

Cells

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a dismal prognosis. Here, we show how an inhibition of de novo dNTP synthesis by the ribonucleotide reductase (RNR) inhibitor hydroxyurea and an inhibition of epigenetic modifiers of the histone deacetylase (HDAC) family affect short-term cultured primary murine PDAC cells. We used clinically relevant doses of hydroxyurea and the class 1 HDAC inhibitor entinostat. We analyzed the cells by flow cytometry and immunoblot. Regarding the induction of apoptosis and DNA replication stress, hydroxyurea and the novel RNR inhibitor COH29 are superior to the topoisomerase-1 inhibitor irinotecan which is used to treat PDAC. Entinostat promotes the induction of DNA replication stress by hydroxyurea. This is associated with an increase in the PP2A subunit PR130/PPP2R3A and a reduction of the ribonucleotide reductase subunit RRM2 and the DNA repair protein RAD51. We further show that class 1 HDAC activity promotes the hydroxyurea-induced activation of the checkpoint kinase ataxia-telangiectasia mutated (ATM). Unlike in other cell systems, ATM is pro-apoptotic in hydroxyurea-treated murine PDAC cells. These data reveal novel insights into a cytotoxic, ATM-regulated, and HDAC-dependent replication stress program in PDAC cells.

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“…On the one hand, YAP/TAZ are required for the recruitment of BRD4 on a broad range of enhancers and promoters of genes supporting cells proliferation and metabolism [37]. On the other hand, YAP/TAZ may support hyper-transcription by co-adjuvating the activity of growth controlling oncogenic TFs, such as E2Fs and MYC [37,56,126,129]. Indeed, genomic studies indicate that MYC could recruit YAP on a large fraction of its target genes, thus boosting MYC-dependent transcriptional output (and MYC oncogenic function) [45].…”

Section: Hyper-transcription and Transcriptional Addictionmentioning

confidence: 99%

Emerging Principles in the Transcriptional Control by YAP and TAZ

López-Hernández

Sberna

Campaner

2021

Cancers

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Yes-associated protein (YAP) and TAZ are transcriptional cofactors that sit at the crossroad of several signaling pathways involved in cell growth and differentiation. As such, they play essential functions during embryonic development, regeneration, and, once deregulated, in cancer progression. In this review, we will revise the current literature and provide an overview of how YAP/TAZ control transcription. We will focus on data concerning the modulation of the basal transcriptional machinery, their ability to epigenetically remodel the enhancer–promoter landscape, and the mechanisms used to integrate transcriptional cues from multiple pathways. This reveals how YAP/TAZ activation in cancer cells leads to extensive transcriptional control that spans several hallmarks of cancer. The definition of the molecular mechanism of transcriptional control and the identification of the pathways regulated by YAP/TAZ may provide therapeutic opportunities for the effective treatment of YAP/TAZ-driven tumors.

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Hypertranscription and replication stress in cancer

Abstract: Hypertranscription is defined as a relative increase in global transcription to support proliferation and cell growth.

Cited by 50 publications

References 142 publications

Decoding Cancer Variants of Unknown Significance for Helicase–Nuclease–RPA Complexes Orchestrating DNA Repair During Transcription and Replication

Decoding Cancer Variants of Unknown Significance for Helicase–Nuclease–RPA Complexes Orchestrating DNA Repair During Transcription and Replication

Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion

Emerging Principles in the Transcriptional Control by YAP and TAZ

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