RECQ5 helicase promotes resolution of conflicts between replication and transcription in human cells

Urban, Václav; Dobrovolná, Jana; Hühn, D; Fryzelkova, Jana; Bártek, Jiří; Janscak, Pavel

doi:10.1083/jcb.201507099

Cited by 72 publications

(74 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, MRN loss reduces PCNA ubiquitination and is epistatic with knockdown of RAD18, an E3 ubiquitin ligase for PCNA and known activator of the FA pathway 43 . These observations are consistent with the literature in the context of DNA damage repair, where RAD18 requires RECQL5 binding to stimulate PCNAubiquitination 47 , and where RECQL5 recruitment to damage sites is dependent on the MRN complex 48 . Our data coalesces with the literature in a model where MRN is an early actor at R-loop stalled forks, and coordinates the recruitment of FA pathway components through a cascade of events ( Fig.…”

Section: Discussionsupporting

confidence: 92%

MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

Chang

Wells

Tsai

et al. 2018

Preprint

View full text Add to dashboard Cite

Ectopic R-loop accumulation causes DNA replication stress and genome instability. To avoid these outcomes, cells possess a range of anti-R-loop mechanisms, including RNaseH that degrades the RNA moiety in R-loops. To comprehensively identify anti-R-loop mechanisms, we performed a genome-wide trigenic interaction screen in yeast lacking RNH1 and RNH201. We identified >100 genes critical for fitness in the absence of RNaseH, which were enriched for DNA replication fork maintenance factors such as RAD50. We show in yeast and human cells that R-loops accumulate during RAD50 depletion. In human cancer cell models, we find that RAD50 and its partners in the MRE11-RAD50-NBS1 complex regulate R-loop-associated DNA damage and replication stress. We show that a non-nucleolytic function of MRE11 is important for R-loop suppression via activation of PCNA-ubiquitination by RAD18 and recruiting anti-R-loop helicases in the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms of transcription-replication conflicts.

show abstract

Section: Discussionsupporting

confidence: 92%

MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

Chang

Wells

Tsai

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Two of them, c.233C>T, p.Pro78Leu and c.539G>A, p.Arg180His were located in the helicase domain of RECQL5 and we demonstrated that they affected its activity by using a functional assay previously described (Figure ; Newman et al, ). It has been reported that the helicase activity of RECQL5 is necessary to exert its function in the resolution of replication‐transcription conflicts and the prevention of spurious HR (Urban et al, ). Taking into account that most BC susceptibility genes described so far are directly or indirectly involved in HR, we propose that variants in RECQL5 affecting HR regulation could be associated with BC risk, although further functional assays testing the actual effect on altering the DNA would be necessary to draw more definite conclusions.…”

Section: Discussionmentioning

confidence: 99%

RECQL5: Another DNA helicase potentially involved in hereditary breast cancer susceptibility

et al. 2019

View full text Add to dashboard Cite

There is still around 50% of the familial breast cancer (BC) cases with an undefined genetic cause, here we have used next-generation sequencing (NGS) technology to identify new BC susceptibility genes. This approach has led to the identification of RECQL5, a member of RECQL-helicases family, as a new BC susceptibility candidate, which deserves further study. We have used a combination of whole exome sequencing in a family negative for mutations in BRCA1/2 throughout (BRCAX), in which we found a probably deleterious variant in RECQL5, and targeted NGS of the complete coding regions and exon-intron boundaries of the candidate gene in 699 BC Spanish BRCAX families and 665 controls. Functional characterization and in silico inference of pathogenicity were performed to evaluate the deleterious effect of detected variants. We found at least seven deleterious or likely deleterious variants among the cases and only one in controls. These results prompt us to propose RECQL5 as a gene that would be worth to analyze in larger studies to explore its possible implication in BC susceptibility. K E Y W O R D S breast cancer, germline pathogenic variant, RECQL5, whole exome sequencing Human Mutation. 2019;40:566-577. wileyonlinelibrary.com/journal/humu 566 |

show abstract

“…Whether this coordination is actively enforced by trans-acting factors, especially within CFSs that are prone to transcription stress, remains an important question. One known factor acting on the conflict resolution is RECQL5, a DNA helicase that associates with both RNAPII and PCNA (43–45); of note, RECQL5 depletion leads to uncontrolled elongation of RNAPII, with higher levels of RNAPII pausing and arrest globally at the transcription regions (45). We postulate that BMI1 and RNF2 may impose similar control over RNAPII elongation at CFSs.…”

Section: Discussionmentioning

confidence: 99%

Transcription-replication conflicts as a source of common fragile site instability caused by BMI1-RNF2 deficiency

Sanchez

Vivo

Tonzi

et al. 2019

Preprint

View full text Add to dashboard Cite

Common fragile sites (CFSs) are breakage-prone genomic loci, and are considered to be hotspots for genomic rearrangements frequently observed in cancers. Understanding the underlying mechanisms for CFS instability will lead to better insight on cancer etiology. Here we show that Polycomb group proteins BMI1 and RNF2 are suppressors of transcription-replication conflicts (TRCs) and CFS instability. Cells depleted of BMI1 or RNF2 showed slower replication forks and elevated fork stalling. These phenotypes are associated with increase occupancy of RNA Pol II (RNAPII) at CFSs, suggesting that the BMI1-RNF2 complex regulate RNAPII elongation at these fragile regions. Using proximity ligase assays, we showed that depleting BMI1 or RNF2 causes increased associations between RNAPII with EdU-labeled nascent forks and replisomes, suggesting increased TRC incidences. Increased occupancy of a fork protective factor FANCD2 and R-loop resolvase RNH1 at CFSs are observed in RNF2 CRISPR-KO cells, which are consistent with increased transcription-associated replication stress in RNF2-deficient cells. Depleting FANCD2 or FANCI proteins further increased genomic instability and cell death of the RNF2-deficient cells, suggesting that in the absence of RNF2, cells depend on these fork-protective factors for survival. These data suggest that the Polycomb proteins have non-canonical roles in suppressing TRC and preserving genomic integrity.Author summaryIncreasing evidence suggest that instabilities at common fragile sites (CFSs), breakage-prone genomic loci, may be source of genomic aberration seen in cancer cells. Among the proposed mechanisms that can cause CFSs instabilities is the conflict between transcription and replication, and the mechanisms or factors that resolve the possible conflicts are only beginning to be understood. Here we found that deficiency in the Polycomb group proteins BMI1 or RNF2 leads to the CFS instability, and is associated with transcription-associated replication fork stresses. We further found that in the absence of RNF2, cells depend on the Fanconi Anemia fork-protective proteins for genome maintenance and survival. These results underscore that the Polycomb proteins are important for genome maintenance.

show abstract

RECQ5 helicase promotes resolution of conflicts between replication and transcription in human cells

Abstract: Urban et al. show that RECQ5 DNA helicase promotes RAD18-dependent PCNA ubiquitination and the processing of replication intermediates upon collisions between replication and transcription complexes.

Cited by 72 publications

References 37 publications

MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

RECQL5: Another DNA helicase potentially involved in hereditary breast cancer susceptibility

Transcription-replication conflicts as a source of common fragile site instability caused by BMI1-RNF2 deficiency

Contact Info

Product

Resources

About