Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability

Prendergast, Lisa; McClurg, Urszula L.; Hristova, Rumyana; Berlinguer‐Palmini, Rolando; Greener, Sarah; Veitch, Katie; Hernández, Inmaculada; Pasero, Philippe; Rico, Daniel; Higgins, Jonathan M.G.; Gospodinov, Anastas; Papamichos‐Chronakis, Manolis

doi:10.1038/s41467-020-18306-x

Cited by 71 publications

(63 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another potential explanation for transcription-dependent instability of large genes invokes R-loop formation that conflicts with replication progression ( 18 , 63 , 64 ). We addressed this hypothesis by an experimental approach we previously used to establish many properties of CNV hotspots ( 2–5 ).…”

Section: Resultsmentioning

confidence: 99%

Locus-specific transcription silencing at the FHIT gene suppresses replication stress-induced copy number variant formation and associated replication delay

Park

Bennett-Baker

Ahmed

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

Impaired replication progression leads to de novo copy number variant (CNV) formation at common fragile sites (CFSs). We previously showed that these hotspots for genome instability reside in late-replicating domains associated with large transcribed genes and provided indirect evidence that transcription is a factor in their instability. Here, we compared aphidicolin (APH)-induced CNV and CFS frequency between wild-type and isogenic cells in which FHIT gene transcription was ablated by promoter deletion. Two promoter-deletion cell lines showed reduced or absent CNV formation and CFS expression at FHIT despite continued instability at the NLGN1 control locus. APH treatment led to critical replication delays that remained unresolved in G2/M in the body of many, but not all, large transcribed genes, an effect that was reversed at FHIT by the promoter deletion. Altering RNase H1 expression did not change CNV induction frequency and DRIP-seq showed a paucity of R-loop formation in the central regions of large genes, suggesting that R-loops are not the primary mediator of the transcription effect. These results demonstrate that large gene transcription is a determining factor in replication stress-induced genomic instability and support models that CNV hotspots mainly result from the transcription-dependent passage of unreplicated DNA into mitosis.

show abstract

Section: Resultsmentioning

confidence: 99%

Locus-specific transcription silencing at the FHIT gene suppresses replication stress-induced copy number variant formation and associated replication delay

Park

Bennett-Baker

Ahmed

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…However, INO80 plays an essential role in superenhancer-mediated oncogenic transcription and tumor growth, in both melanoma and non-small-cell lung cancer [ 266 , 267 ]. Interestingly, INO80 counteracts R-loops, promoting DNA replication in the presence of transcription, enabling proliferation in cancers [ 268 ].…”

Section: Dissonances In Chromatin Remodeling In Cancermentioning

confidence: 99%

Sophisticated Conversations between Chromatin and Chromatin Remodelers, and Dissonances in Cancer

Clapier

2021

IJMS

View full text Add to dashboard Cite

The establishment and maintenance of genome packaging into chromatin contribute to define specific cellular identity and function. Dynamic regulation of chromatin organization and nucleosome positioning are critical to all DNA transactions—in particular, the regulation of gene expression—and involve the cooperative action of sequence-specific DNA-binding factors, histone modifying enzymes, and remodelers. Remodelers are molecular machines that generate various chromatin landscapes, adjust nucleosome positioning, and alter DNA accessibility by using ATP binding and hydrolysis to perform DNA translocation, which is highly regulated through sophisticated structural and functional conversations with nucleosomes. In this review, I first present the functional and structural diversity of remodelers, while emphasizing the basic mechanism of DNA translocation, the common regulatory aspects, and the hand-in-hand progressive increase in complexity of the regulatory conversations between remodelers and nucleosomes that accompanies the increase in challenges of remodeling processes. Next, I examine how, through nucleosome positioning, remodelers guide the regulation of gene expression. Finally, I explore various aspects of how alterations/mutations in remodelers introduce dissonance into the conversations between remodelers and nucleosomes, modify chromatin organization, and contribute to oncogenesis.

show abstract

“…Moreover, Ino80C has also been shown to prevent spurious, pervasive transcription around replication origins (49). Ino80C has been shown to localize to R-loop enriched regions in the genome and counteract their formation (50). In addition, Ino80C has been implicated in reducing genomic nucleosome coverage and thereby mobilizing chromosomes in cells experiencing DSBs; this chromosome mobility promotes the homology search required for HR repair (46).…”

Section: Discussionmentioning

confidence: 99%

RNAi and Ino80 complex control rate limiting translocation step that moves rDNA to eroding telomeres

Cooper

Apte

Masuda

et al. 2021

Preprint

View full text Add to dashboard Cite

The discovery of HAATIrDNA, a mode of telomerase-negative survival in which canonical telomeres are replaced with ribosomal DNA (rDNA) repeats that acquire chromosome end-protection capability, raised crucial questions as to how rDNA tracts ‘jump’ to eroding, nonhomologous chromosome ends. Here we show that HAATIrDNA formation is initiated and limited by a single translocation that juxtaposes rDNA from Chromosome (Chr) III onto subtelomeric elements (STE) on Chr I or II; this rare reaction requires the RNAi pathway and the Ino80 nucleosome remodeling complex (Ino80C), thus defining an unforeseen relationship between these two machineries. The unique STE-rDNA junction created by this initial translocation is efficiently copied to the remaining STE chromosome ends, without the need for RNAi or Ino80C, forming HAATIrDNA. Intriguingly, both the RNAi and Ino80C machineries contain a component that plays dual roles in HAATI subtype choice. Dcr1 of the RNAi pathway and Iec1 of the Ino80C both promote HAATIrDNA formation as part of their respective canonical machineries, but both also inhibit formation of the exceedingly rare HAATISTE (in which STE sequences mobilize throughout the genome and assume chromosome end protection capacity) in non-canonical, pathway-independent manners. This work provides a glimpse into a previously unrecognized crosstalk between RNAi and Ino80C in controlling unusual translocation reactions that establish telomere-free linear chromosome ends.

show abstract

Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability

Cited by 71 publications

References 70 publications

Locus-specific transcription silencing at the FHIT gene suppresses replication stress-induced copy number variant formation and associated replication delay

Locus-specific transcription silencing at the FHIT gene suppresses replication stress-induced copy number variant formation and associated replication delay

Sophisticated Conversations between Chromatin and Chromatin Remodelers, and Dissonances in Cancer

RNAi and Ino80 complex control rate limiting translocation step that moves rDNA to eroding telomeres

Contact Info

Product

Resources

About