Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations

Dellino, Gaetano Ivan; Palluzzi, Fernando; Chiariello, Andrea M.; Piccioni, Rossana; Bianco, Simona; Furia, Laura; Conti, Giulia De; Bouwman, Britta A. M.; Melloni, Giorgio; Guido, Davide; Giacò, Luciano; Luzi, Lucilla; Cittaro, Davide; Faretta, Mario; Nicodemi, Mario; Crosetto, Nicola; Pelicci, Pier Giuseppe

doi:10.1038/s41588-019-0421-z

Cited by 88 publications

(85 citation statements)

References 68 publications

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“…Of note, CHD1 is the second most frequently mutated gene in prostate cancer, after PTEN 24,25 . In agreement with our data, Dellino et al recently showed that release of paused RNA Pol II in breast cancer cells induces DSBs preferentially at long genes and can lead to chromosomal translocations 26 .…”

Section: Discussionsupporting

confidence: 94%

Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells

Bulut-Karslıoğlu

Guzman-Ayala

et al. 2019

Preprint

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Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 binds to genes transcribed by RNA Polymerase (Pol) I and II and is required for hypertranscription in embryonic stem (ES) cells in vitro and the early postimplantation epiblast in vivo. Biochemically, Chd1 has been shown to facilitate transcription at least in part by removing nucleosomal barriers to elongation, but its mechanism of action in stem cells remains poorly understood. Here we report a novel role for Chd1 in the repair of promoterproximal endogenous double-stranded DNA breaks (DSBs) in ES cells. An unbiased proteomics approach revealed that Chd1 interacts with several DNA repair factors including Atm, Parp1, Kap1 and Topoisomerase 2b. We show that wild-type ES cells display high levels of phosphorylated H2A.X and Kap1 at chromatin, notably at rDNA in the nucleolus, in a Chd1-dependent manner. Loss of Chd1 leads to an extensive accumulation of DSBs at Chd1bound Pol II-transcribed genes and rDNA. Genes prone to DNA breaks in Chd1 KO ES cells tend to be longer genes with GC-rich promoters, a more labile nucleosomal structure and roles in chromatin regulation, transcription and signaling. These results reveal a vulnerability of hypertranscribing stem cells to endogenous DNA breaks, with important implications for developmental and cancer biology.

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Section: Discussionsupporting

confidence: 94%

Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells

Bulut-Karslıoğlu

Guzman-Ayala

et al. 2019

Preprint

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“…TOP1 activity at paused RNA Pol II is enhanced by the BRD4dependent phosphorylation of RNA Pol II CTD (60). Transcriptional pausing has been associated with DSBs formation and TOP2 activities (61)(62)(63)(64). Furthermore, G4 motifs correlate with promoter-proximal transcriptional pausing in human genes (19).…”

Section: Top2-dependent Dsbs Induced By G4 Stabilizers Are Countered mentioning

confidence: 99%

Transcription-associated topoisomerase activities control DNA-breaks production by G-quadruplex ligands

Pipier

Bossaert

Riou

et al. 2020

Preprint

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G-quadruplexes (G4), non-canonical DNA structures, are involved in several essential processes. Stabilization of G4 structures by small compounds (G4 ligands) affects almost all DNA transactions, including telomere maintenance and genomic stability. Here, thanks to a powerful and unbiased genetic approach, we identify topoisomerase 2-alpha (TOP2A) as the main effector of cell cytotoxicity induced by CX5461, a G4 ligand currently undergoing phase I/II clinical trials. This approach also allowed to identify new point mutations affecting TOP2A activity without compromising cell viability. Moreover, based on cross-resistance studies and siRNA-based protein depletion we report that TOP2A plays a major role in cell cytotoxicity induced by two unrelated clastogenic G4 ligands, CX5461 and pyridostatin (PDS). We also report that cytotoxic effects induced by both compounds are associated with topoisomerase 2mediated DNA breaks production. Finally, we show that TOP2-mediated DNA breaks production is strongly associated with RNA Pol II-dependent transcription and is countered by topoisomerase 1 (TOP1). Altogether our results indicate that clastogenic G4 ligands act as DNA structure-driven TOP2-poisons at transcribed regions bearing G-quadruplex structures.

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“…Thus, policy and guidelines in Europe have to work in the direction of the abolition of risk behaviors and the promotion of disease prevention. Dellino and colleagues' evidence on cellular life send a message affirming that the avoidance of risk behaviors can increase well‐being and health. So what is the role of “chance” in cancer onset?…”

Section: Change What You Can Manage What You Can'tmentioning

confidence: 99%

“…Cancer often strikes people who follow all the rules of healthy living and have no family history of the disease, prompting the pained question “Why me?” Tomasetti and Vogelstein believe the answer to this question rests in random DNA copying errors . Dellino and colleagues say that these DNA copying errors could be the same mechanisms described in their contribution and thus “controllable” by the cell environment. These controversies highlight that what we currently call “chance” is simply something very complex on biological and organic levels, something we do not know yet, and that the research will allow us to investigate and control in the future.…”

Section: Change What You Can Manage What You Can'tmentioning

confidence: 99%

“…Recent research emphasizes the role of environmental factors in the emergence of oncological diseases. Specifically, Dellino and colleagues demonstrated that cancer‐associated translocations in cells are influenced by the environment they are in, which in turn is influenced by the environment where the full organism lives. Broadly speaking, this “environment” could be conceptualized as the individual's lifestyle choices, such as smoking, food intake, and being more or less healthy.…”

Section: Introductionmentioning

confidence: 99%

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“You do not get cancer by chance”: Communicating the role of environmental causes in cancer diseases and the risk of a “guilt rhetoric”

et al. 2019

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Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations

Cited by 88 publications

References 68 publications

Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells

Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells

Transcription-associated topoisomerase activities control DNA-breaks production by G-quadruplex ligands

“You do not get cancer by chance”: Communicating the role of environmental causes in cancer diseases and the risk of a “guilt rhetoric”

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