Untangling the crosstalk between BRCA1 and R-loops during DNA repair

Alonso, Marta San Martín; Noordermeer, Sylvie M.

doi:10.1093/nar/gkab178

Cited by 24 publications

(28 citation statements)

References 187 publications

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“…The binding of TERRA by BRCA1 results in the suppression of TERRA transcription and promotes the repair or R-loop associated DNA damage at telomeres ( Vohhodina et al, 2021 ). The association of BRCA1 and R-loops at sites of DNA damage may also occur through NLS mediated interactions ( San Martin Alonso and Noordermeer, 2021 ). In addition to BRCA1, BRCA2 also promotes R-loop processing, which has been shown to be regulated by the helicase DDX5 and RNaseH2 ( D’Alessandro et al, 2018 ; Sessa et al, 2021 ).…”

Section: Rna:dna Hybrids In Double-strand Break Repairmentioning

confidence: 99%

Making Connections: Integrative Signaling Mechanisms Coordinate DNA Break Repair in Chromatin

et al. 2021

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DNA double-strand breaks (DSBs) are hazardous to genome integrity and can promote mutations and disease if not handled correctly. Cells respond to these dangers by engaging DNA damage response (DDR) pathways that are able to identify DNA breaks within chromatin leading ultimately to their repair. The recognition and repair of DSBs by the DDR is largely dependent on the ability of DNA damage sensing factors to bind to and interact with nucleic acids, nucleosomes and their modified forms to target these activities to the break site. These contacts orientate and localize factors to lesions within chromatin, allowing signaling and faithful repair of the break to occur. Coordinating these events requires the integration of several signaling and binding events. Studies are revealing an enormously complex array of interactions that contribute to DNA lesion recognition and repair including binding events on DNA, as well as RNA, RNA:DNA hybrids, nucleosomes, histone and non-histone protein post-translational modifications and protein-protein interactions. Here we examine several DDR pathways that highlight and provide prime examples of these emerging concepts. A combination of approaches including genetic, cellular, and structural biology have begun to reveal new insights into the molecular interactions that govern the DDR within chromatin. While many questions remain, a clearer picture has started to emerge for how DNA-templated processes including transcription, replication and DSB repair are coordinated. Multivalent interactions with several biomolecules serve as key signals to recruit and orientate proteins at DNA lesions, which is essential to integrate signaling events and coordinate the DDR within the milieu of the nucleus where competing genome functions take place. Genome architecture, chromatin structure and phase separation have emerged as additional vital regulatory mechanisms that also influence genome integrity pathways including DSB repair. Collectively, recent advancements in the field have not only provided a deeper understanding of these fundamental processes that maintain genome integrity and cellular homeostasis but have also started to identify new strategies to target deficiencies in these pathways that are prevalent in human diseases including cancer.

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Section: Rna:dna Hybrids In Double-strand Break Repairmentioning

confidence: 99%

Making Connections: Integrative Signaling Mechanisms Coordinate DNA Break Repair in Chromatin

et al. 2021

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“…R-loops have been shown to trigger non-canonical and extensive resections [35] and to regulate the RAD51 nucleofilament assembly also through non-canonical mechanisms that rely on Cockayne Syndrome group B (CSB) and RAD52 instead of BRCA1 and BRCA2 [109,145]. R-loops seems to recruit repair proteins underscoring a beneficial role in repair through non-canonical mechanisms which need to be timely and strictly regulated to be ultimately compatible with the unavoidable removal of RNA:DNA hybrids to allow maintenance of genome integrity [146,147].…”

Section: The Enigmatic Role Of Rna:dna Hybrids In Dna Repairmentioning

confidence: 99%

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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“…A plethora of evidence now exists implicating BRCA1 in DNA double-strand break (DSB) repair and genome stability. BRCA1 is comprised of several functional domains that interact with different proteins [ 21 ]. The Really Interesting New Gene (RING) domain at the N-terminus of BRCA1 is crucial for its heterodimerization with BRCA1 -associated RING domain 1 (BARD1) [ 22 ].…”

Section: Brca1 Structure and Function In Dna Double-strand Break Repairmentioning

confidence: 99%

“…The Really Interesting New Gene (RING) domain at the N-terminus of BRCA1 is crucial for its heterodimerization with BRCA1 -associated RING domain 1 (BARD1) [ 22 ]. BRCA1 -BARD1 interaction has been shown to be important for BRCA1 stability [ 21 , 23 ]. In addition, BRCA1 , a RING E3 ubiquitin ligase, is known to ubiquitylate several factors, including histones H2A and H2AX, RNA polymerase II, Estrogen receptor (ER) α, and Hippo signaling protein NF2, among others [ 24 , 25 ].…”

Section: Brca1 Structure and Function In Dna Double-strand Break Repairmentioning

confidence: 99%

BRCA1 and Metastasis: Outcome of Defective DNA Repair

Krishnan

Patel

Hakem

2021

Cancers

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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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Untangling the crosstalk between BRCA1 and R-loops during DNA repair

Cited by 24 publications

References 187 publications

Making Connections: Integrative Signaling Mechanisms Coordinate DNA Break Repair in Chromatin

Making Connections: Integrative Signaling Mechanisms Coordinate DNA Break Repair in Chromatin

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

BRCA1 and Metastasis: Outcome of Defective DNA Repair

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