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

@article{Dellino2019ReleaseOP,
  title={Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations},
  author={Gaetano Ivan Dellino and Fernando Palluzzi and Andrea Maria Chiariello and Rossana Piccioni and Simona Bianco and Laura Furia and Giulia De Conti and Britta A.M. Bouwman and Giorgio E. M. Melloni and Davide Guido and Luciano Giac{\'o} and Lucilla Luzi and Davide Cittaro and Mario Faretta and Mario Nicodemi and Nicola Crosetto and Pier Giuseppe Pelicci},
  journal={Nature Genetics},
  year={2019},
  volume={51},
  pages={1011-1023}
}
It is not clear how spontaneous DNA double-strand breaks (DSBs) form and are processed in normal cells, and whether they predispose to cancer-associated translocations. We show that DSBs in normal mammary cells form upon release of paused RNA polymerase II (Pol II) at promoters, 5′ splice sites and active enhancers, and are processed by end-joining in the absence of a canonical DNA-damage response. Logistic and causal-association models showed that Pol II pausing at long genes is the main… 
Pausing sites of RNA polymerase II on actively transcribed genes are enriched in DNA double-stranded breaks
TLDR
Using genome-wide DNA break mapping/sequencing techniques at single-nucleotide resolution in human cells, it is found that DSBs are preferentially located around transcription start sites of highly transcribed and paused genes and that Pol II promoter-proximal pausing sites are enriched in D SBs.
A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation
TLDR
It is reported that upon excessive RNA:DNA hybrid accumulation, DNA synthesis is enhanced at DSBs, in a manner that depends on BLM and POLD3, and highlights the toxic potential of RNA: DNA hybrids that accumulate at transcription-associated DSBS.
BLM-dependent Break-Induced Replication handles DSBs in transcribed chromatin upon impaired RNA:DNA hybrids dissolution
TLDR
A critical function of the Bloom RecQ DNA helicase (BLM) in TC-DSBR in human cells is uncovered, which unveils a role for BLM in BIR at DSBs in active chromatin, and highlights the toxic potential of RNA:DNA hybrids that accumulate at these transcription-associated D SBs.
Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells
TLDR
A novel role for Chd1 is reported in the repair of promoter-proximal endogenous double-stranded DNA breaks (DSBs) in ES cells, revealing a vulnerability of hypertranscribing stem cells to endogenous DNA breaks, with important implications for developmental and cancer biology.
Canonical non-homologous end-joining promotes genome mutagenesis and translocations induced by transcription-associated DNA topoisomerase 2 activity
TLDR
It is shown that TOP2-induced genome instability is mediated by mutagenic canonical non-homologous end joining whereas homologous recombination protects cells against these insults, with relevant implications for chemotherapy.
Control of RNA polymerase II promoter-proximal pausing by DNA supercoiling
TLDR
The control of promoter DNA supercoiling by topoisomerases is described as a novel layer for the regulation of gene expression, which can act as a molecular switch to rapidly activate transcription.
Topoisomerase II contributes to DNA secondary structure-mediated double-stranded breaks
TLDR
A direct role for TOP2 is revealed in generating secondary structure-mediated DNA fragility, advancing the understanding of mechanisms underlying human genome instability.
DNA Double Strand Breaks and Chromosomal Translocations Induced by DNA Topoisomerase II
TLDR
The origin of recombinogenic TOP2 breaks and the determinants behind their tendency to translocate will be summarized.
CNCC: An analysis tool to determine genome-wide DNA break end structure at single-nucleotide resolution
TLDR
The use of a coverage-normalized cross correlation analysis (CNCC) to process high-precision genome-wide break mapping data, and determine genome- wide break end structure distributions at single-nucleotide resolution is described.
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References

SHOWING 1-10 OF 71 REFERENCES
A localized nucleolar DNA damage response facilitates recruitment of the homology-directed repair machinery independent of cell cycle stage.
TLDR
It is suggested that HR can be templated in cis and suggest a role for chromosomal context in the maintenance of NOR genomic stability.
Classical non-homologous end-joining pathway utilizes nascent RNA for error-free double-strand break repair of transcribed genes
TLDR
It is reported that during such DSBR, mammalian C-NHEJ proteins form a multiprotein complex with RNA polymerase II and preferentially associate with the transcribed genes after DSB induction, allowing error-free DSBR in transcribed but not in non-transcribed genes.
Transcriptional elongation requires DNA break-induced signalling
TLDR
It is proposed that DDR signalling is required for effective Pol II pause release and transcriptional elongation through a novel mechanism involving TRIM28, DNA-PK and topoisomerase II.
Transcription-associated processes cause DNA double-strand breaks and translocations in neural stem/progenitor cells
TLDR
High-throughput, genome-wide translocation sequencing studies of activated B cells have revealed that DNA double-strand breaks capable of translocating to defined bait DSBs are enriched around the transcription start sites (TSSs) of active genes, and the HTGTS approach is used to investigate whether this phenomenon occurs in primary neural stem/progenitor cells (NSPCs).
Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair
TLDR
The functional importance of ATM kinase activity and phosphorylation in the response to DSBs is demonstrated, and a model in which ordered chromatin structure changes that occur after DNA breakage depend on functional NBS1 and ATM, and facilitate DNA DSB repair is supported.
High‐resolution profiling of γH2AX around DNA double strand breaks in the mammalian genome
TLDR
It is found that all DSBs trigger large γH2AX domains, which spread out from the DSB in a bidirectional, discontinuous and not necessarily symmetrical manner, which is the first genome‐wide mapping of γh2AX around D SBs, indicating that mechanisms may exist to protect gene transcription from γ H2AX spreading and from the chromatin rearrangements induced by DSBS.
Transcription forms and remodels supercoiling domains unfolding large-scale chromatin structures
TLDR
It is suggested that supercoiling domains create a topological environment that facilitates gene activation, providing an evolutionary purpose for clustering genes along chromosomes.
A Topoisomerase IIß-Mediated dsDNA Break Required for Regulated Transcription
TLDR
It is reported that the signal-dependent activation of gene transcription by nuclear receptors and other classes of DNA binding transcription factors, including activating protein 1, requires DNA topoisomerase IIβ-dependent, transient, site-specific dsDNA break formation.
...
1
2
3
4
5
...