RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors

Patel, Parasvi S.; Abraham, Karan Joshua; Guturi, Kiran Kumar Naidu; Halaby, Marie-Jo; Khan, Zahra; Palomero, Luís; Ho, Brandon; Duan, Shili; St-Germain, Jonathan; Algouneh, Arash; Mateo, Francesca; Ghamrasni, Samah El; Barbour, Haithem; Barnes, Daniel R.; Beesley, Jonathan; Sánchez, Otto; Berman, Hal K.; Brown, Grant W.; Affar, El Bachir; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Arrowsmith, C.H.; Raught, Brian; Pujana, Miquel Àngel; Mekhail, Karim; Hakem, Anne; Hakem, Razqallah

doi:10.1172/jci140105

Cited by 44 publications

(31 citation statements)

References 56 publications

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“…The loss of RNF168 results in an impairment of DHX9 activity, thus abrogating its role in R-loop resolution. Moreover, using mouse models it was shown that Rnf168 depletion protects against Brca1-mutated mammary tumorigenesis, and this data is further corroborated by the identification of a human genetic variant that reduces breast cancer risk in BRCA1-mutation carriers when they are associated with reduced RNF168 expression levels [164]. Together, these results bring to light the existence of a factor that indirectly, by promoting DHX9 recruitment, resolves R-loops accumulation (Figure 4).…”

Section: Rnf168mentioning

confidence: 65%

“…RNF168 is well known to mediate K63-mediated ubiquitination of p53 Binding Protein 1 (53BP1) and of H2A histones at K13-15, both required marks for recruitment and retention of 53BP1 at DNA damage sites [190,191]. However, a recent study has demonstrated that loss of RNF168 results in R-loop accumulation in BRCA1/2-mutant cancer cells, leading to DSBs accumulation, senescence and cell death [164]. In this study, using interactome assays, RNF168 was identified as interacting partner with DHX9, an RNA/DNA helicase that is involved in the resolution and removal of R-loops, as mentioned above [111,164].…”

Section: Rnf168mentioning

confidence: 99%

“…However, a recent study has demonstrated that loss of RNF168 results in R-loop accumulation in BRCA1/2-mutant cancer cells, leading to DSBs accumulation, senescence and cell death [164]. In this study, using interactome assays, RNF168 was identified as interacting partner with DHX9, an RNA/DNA helicase that is involved in the resolution and removal of R-loops, as mentioned above [111,164]. RNF168 directly ubiquitinates DHX9 at K697 and K708 aiding its recruitment at R-loop-forming loci.…”

Section: Rnf168mentioning

confidence: 99%

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R-Loops and Its Chro-Mates: The Strange Case of Dr. Jekyll and Mr. Hyde

Uruci

Wheeler

et al. 2021

IJMS

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Since their discovery, R-loops have been associated with both physiological and pathological functions that are conserved across species. R-loops are a source of replication stress and genome instability, as seen in neurodegenerative disorders and cancer. In response, cells have evolved pathways to prevent R-loop accumulation as well as to resolve them. A growing body of evidence correlates R-loop accumulation with changes in the epigenetic landscape. However, the role of chromatin modification and remodeling in R-loops homeostasis remains unclear. This review covers various mechanisms precluding R-loop accumulation and highlights the role of chromatin modifiers and remodelers in facilitating timely R-loop resolution. We also discuss the enigmatic role of RNA:DNA hybrids in facilitating DNA repair, epigenetic landscape and the potential role of replication fork preservation pathways, active fork stability and stalled fork protection pathways, in avoiding replication-transcription conflicts. Finally, we discuss the potential role of several Chro-Mates (chromatin modifiers and remodelers) in the likely differentiation between persistent/detrimental R-loops and transient/benign R-loops that assist in various physiological processes relevant for therapeutic interventions.

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Section: Rnf168mentioning

confidence: 65%

Section: Rnf168mentioning

confidence: 99%

Section: Rnf168mentioning

confidence: 99%

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R-Loops and Its Chro-Mates: The Strange Case of Dr. Jekyll and Mr. Hyde

Uruci

Wheeler

et al. 2021

IJMS

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“…Over recent years, many additional DEAD-box RNA helicases have been added to this list of RNA/DNA helicases that can process R-loops. These include DHX9, DDX1, DDX3, DDX5, DDX19, DDX21, DDX23, DDX39B, DDX43, DDX47 and DDX56 [ 103 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 ]. TonEBP was also recently identified as an R-loop sensor and shown to recruit the RNA methyltransferase-like 3 (MTLL3) specifically to N6-methyladenosine (m6A) methylated R-loops [ 153 , 154 ].…”

Section: Mechanisms To Resolve a Trcmentioning

confidence: 99%

Consequences and Resolution of Transcription–Replication Conflicts

Lalonde

Trauner

Werner

et al. 2021

Life

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Transcription–replication conflicts occur when the two critical cellular machineries responsible for gene expression and genome duplication collide with each other on the same genomic location. Although both prokaryotic and eukaryotic cells have evolved multiple mechanisms to coordinate these processes on individual chromosomes, it is now clear that conflicts can arise due to aberrant transcription regulation and premature proliferation, leading to DNA replication stress and genomic instability. As both are considered hallmarks of aging and human diseases such as cancer, understanding the cellular consequences of conflicts is of paramount importance. In this article, we summarize our current knowledge on where and when collisions occur and how these encounters affect the genome and chromatin landscape of cells. Finally, we conclude with the different cellular pathways and multiple mechanisms that cells have put in place at conflict sites to ensure the resolution of conflicts and accurate genome duplication.

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“…Thus, treatment strategies that eliminate BRCA1/2 -mutant tumors are likely to have a substantial impact on various cancer types and reducing the global cancer burden. Though Poly (ADP-ribose) polymerase (PARP) inhibition is at the forefront of BRCA1/2 -mutant breast and ovarian cancer therapy, many new exciting targets such as POLQ, RAD52, FANCD2, FEN1, APEX2, and RNF168, appear to have therapeutic potential in pre-clinical studies [ 12 , 13 , 14 , 15 , 16 ]. These are reviewed in detail elsewhere [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

BRCA1 and Metastasis: Outcome of Defective DNA Repair

Krishnan

Patel

Hakem

2021

Cancers

Self Cite

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Heritable mutations in BRCA1 and BRCA2 genes are a major risk factor for breast and ovarian cancer. Inherited mutations in BRCA1 increase the risk of developing breast cancers by up to 72% and ovarian cancers by up to 69%, when compared to individuals with wild-type BRCA1. BRCA1 and BRCA2 (BRCA1/2) are both important for homologous recombination-mediated DNA repair. The link between BRCA1/2 mutations and high susceptibility to breast cancer is well established. However, the potential impact of BRCA1 mutation on the individual cell populations within a tumor microenvironment, and its relation to increased aggressiveness of cancer is not well understood. The objective of this review is to provide significant insights into the mechanisms by which BRCA1 mutations contribute to the metastatic and aggressive nature of the tumor cells.

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RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors

Cited by 44 publications

References 56 publications

R-Loops and Its Chro-Mates: The Strange Case of Dr. Jekyll and Mr. Hyde

R-Loops and Its Chro-Mates: The Strange Case of Dr. Jekyll and Mr. Hyde

Consequences and Resolution of Transcription–Replication Conflicts

BRCA1 and Metastasis: Outcome of Defective DNA Repair

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