BLM helicase suppresses recombination at G-quadruplex motifs in transcribed genes

Wietmarschen, Niek van; Merzouk, Sarra; Halsema, Nancy; Spierings, Diana C. J.; Guryev, Victor; Lansdorp, Peter M.

doi:10.1101/173252

Cited by 18 publications

(22 citation statements)

References 64 publications

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“…Given the high prevalence of G4 at promoters and transcribed loci (Hänsel-Hertsch et al, 2016) this raises the interesting possibility that BLM may be a bona fide component of TC-DSBR which activity may be particularly relevant at transcribed, G4-forming, damaged loci. In agreement, Strand-seq experiments revealed that sister chromatid exchange (SCEs) breakpoints observed in BLM-deficient cells are biased toward G4 motifs, especially those present in transcribed genes (van Wietmarschen et al, 2018).…”

Section: Introductionsupporting

confidence: 54%

BLM-dependent Break-Induced Replication handles DSBs in transcribed chromatin upon impaired RNA:DNA hybrids dissolution

Cohen

Guénolé

Marnef

et al. 2020

Preprint

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Transcriptionally active loci are particularly prone to breakage and mounting evidence suggest that DNA Double-Strand Breaks arising in genes are handled by a dedicated repair pathway, Transcription-Coupled DSB Repair (TC-DSBR), that entails R-loops accumulation and dissolution. Here, we uncovered a critical function of the Bloom RecQ DNA helicase (BLM) in TC-DSBR in human cells. BLM is recruited in a transcription dependent-manner at DSBs where it fosters resection, RAD51 binding and accurate Homologous Recombination repair. However, in a R-loop dissolution-deficient background BLM switches from promoting Homologous Recombination to promoting Break-Induced Replication (BIR), which strongly impairs cell viability. Altogether our

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Section: Introductionsupporting

confidence: 54%

BLM-dependent Break-Induced Replication handles DSBs in transcribed chromatin upon impaired RNA:DNA hybrids dissolution

Cohen

Guénolé

Marnef

et al. 2020

Preprint

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“…Aberrant function of the G4-resolving helicases WRN and BLM result in altered transcription of genes containing G4 motifs in their promoter region, corroborating a link between G4s and transcription [107,108]. Moreover, BLM-mutated cells derived from Bloom syndrome patients show high rates of sister chromatid exchange at sites of G4 motifs in transcribed genes [109]. Notably, these helicases also process duplex DNA, so not all the observed changes may be linked to G4 structures.…”

Section: Biological Role Of G4smentioning

confidence: 91%

The Structure and Function of DNA G-Quadruplexes

Spiegel

Adhikari

Balasubramanian

2020

Trends in Chemistry

590

568

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Guanine-rich DNA sequences can fold into four-stranded, noncanonical secondary structures called G-quadruplexes (G4s). G4s were initially considered a structural curiosity, but recent evidence suggests their involvement in key genome functions such as transcription, replication, genome stability, and epigenetic regulation, together with numerous connections to cancer biology. Collectively, these advances have stimulated research probing G4 mechanisms and consequent opportunities for therapeutic intervention. Here, we provide a perspective on the structure and function of G4s with an emphasis on key molecules and methodological advances that enable the study of G4 structures in human cells. We also critically examine recent mechanistic insights into G4 biology and protein interaction partners and highlight opportunities for drug discovery. Beyond the DNA Double HelixA chemist's perspective on the function of a molecule, or a system of molecules, is typically led by a consideration of how molecular structure dictates function. The most widely recognised DNA structure is that of the classical DNA double helix [1], which defines a structural basis for the genetic code via defined base-pairing. Yet, it is evident that DNA is structurally dynamic and capable of adopting alternative secondary structures. One such class of DNA secondary structure is the four-stranded Gquadruplex (G4). Herein, we discuss some of the key scientific history that has shaped our understanding of this structural motif, its probable functions in biology, and major unanswered questions that remain to be solved.

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“…In proliferating cells, G4 act as replication fork barriers, provoking fork collapses, the activation of the DNA damage response and the induction of replication-dependent DSBs (13). However, increasing evidence indicates also a significant impact of G4 structures on genomic stability through transcriptiondependent processes (5,(14)(15)(16).…”

Section: Introductionmentioning

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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BLM helicase suppresses recombination at G-quadruplex motifs in transcribed genes

Cited by 18 publications

References 64 publications

BLM-dependent Break-Induced Replication handles DSBs in transcribed chromatin upon impaired RNA:DNA hybrids dissolution

BLM-dependent Break-Induced Replication handles DSBs in transcribed chromatin upon impaired RNA:DNA hybrids dissolution

The Structure and Function of DNA G-Quadruplexes

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

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