BRCA1 and RNAi factors promote repair mediated by small RNAs and PALB2–RAD52

Hatchi, Elodie; Goehring, Liana; Landini, Serena; Skourti-Stathaki, Konstantina; DeConti, Derrick K.; Abderazzaq, Fieda; Banerjee, Priyankana; Demers, Timothy M.; Wang, Yaoyu E.; Quackenbush, John; Livingston, David M.

doi:10.1038/s41586-020-03150-2

Cited by 33 publications

(17 citation statements)

References 53 publications

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“…Alternatively, replication or transcription stress in repetitive genomic regions may lead to DNA damage that requires RDN2 and TWI8 for proper repair, similar to a role for RNAi in Neurospora crassa in promoting DNA repair at repetitive transgenic loci ( Zhang et al. , 2013 ; Yang and Qi, 2015 ) or in human cells at specific transcription termination sites that form RNA–DNA hybrid structures (R-loops; Hatchi et al. , 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…, 2017 ; Michelini et al. , 2017 ; Hatchi et al. , 2021 ), though RNAi proteins may also have sRNA-independent roles in DSB repair ( Lu et al.…”

Section: Resultsmentioning

confidence: 99%

“…, 2014 ). Moreover, a study in human cells found that overexpression of damage-associated sRNA can increase DNA damage in human cells ( Hatchi et al. , 2021 ).…”

Section: Resultsmentioning

confidence: 99%

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Disruption of a ∼23–24 nucleotide small RNA pathway elevates DNA damage responses in Tetrahymena thermophila

Lee

Pollard

Galati

et al. 2021

MBoC

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Endogenous RNA interference (RNAi) pathways regulate a wide range of cellular processes in diverse eukaryotes, yet in the ciliated eukaryote, Tetrahymena thermophila, the cellular purpose of RNAi pathways that generate ∼23-24 nucleotide (nt) small (s)RNAs has remained unknown. Here, we investigated the phenotypic and gene expression impacts on vegetatively growing cells when genes involved in ∼23-24 nt sRNA biogenesis are disrupted. We observed slower proliferation and increased expression of genes involved in DNA metabolism and chromosome organization and maintenance in sRNA biogenesis mutants RSP1Δ, RDN2Δ, and RDF2Δ. In addition, RSP1Δ and RDN2Δ cells frequently exhibited enlarged chromatin extrusion bodies, which are non-nuclear, DNA-containing structures that may be akin to mammalian micronuclei. Expression of homologous recombination factor Rad51 was specifically elevated in RSP1Δ and RDN2Δ strains, with Rad51 and double-stranded DNA break (DSB) marker γ-H2A.X localized to discrete macronuclear foci. In addition, an increase in Rad51 and γ-H2A.X foci were also found in knockouts of TWI8, a macronucleus-localized PIWI protein. Together, our findings suggest that an evolutionarily conserved role for RNAi pathways in maintaining genome integrity may be extended even to the early branching eukaryotic lineage that gave rise to Tetrahymena thermophila.

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Section: Resultsmentioning

confidence: 99%

“…, 2017 ; Michelini et al. , 2017 ; Hatchi et al. , 2021 ), though RNAi proteins may also have sRNA-independent roles in DSB repair ( Lu et al.…”

Section: Resultsmentioning

confidence: 99%

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Disruption of a ∼23–24 nucleotide small RNA pathway elevates DNA damage responses in Tetrahymena thermophila

Lee

Pollard

Galati

et al. 2021

MBoC

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“…It is not clear whether these sdRNAs are actually derived from R-loops or their vicinity, or if they act in cis or trans. However, this mechanism serves to prevent the genome instability that is associated with R-loop formation [63].…”

Section: Emerging Role Of Snrna In Ddrmentioning

confidence: 99%

Home and Away: The Role of Non-Coding RNA in Intracellular and Intercellular DNA Damage Response

Shaw

Gullerová

2021

Genes

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Non-coding RNA (ncRNA) has recently emerged as a vital component of the DNA damage response (DDR), which was previously believed to be solely regulated by proteins. Many species of ncRNA can directly or indirectly influence DDR and enhance DNA repair, particularly in response to double-strand DNA breaks, which may hold therapeutic potential in the context of cancer. These include long non-coding RNA (lncRNA), microRNA, damage-induced lncRNA, DNA damage response small RNA, and DNA:RNA hybrid structures, which can be categorised as cis or trans based on the location of their synthesis relative to DNA damage sites. Mechanisms of RNA-dependent DDR include the recruitment or scaffolding of repair factors at DNA break sites, the regulation of repair factor expression, and the stabilisation of repair intermediates. DDR can also be communicated intercellularly via exosomes, leading to bystander responses in healthy neighbour cells to generate a population-wide response to damage. Many microRNA species have been directly implicated in the propagation of bystander DNA damage, autophagy, and radioresistance, which may prove significant for enhancing cancer treatment via radiotherapy. Here, we review recent developments centred around ncRNA and their contributions to intracellular and intercellular DDR mechanisms.

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“…BRCA1 has been implicated in protecting stalled replication forks, regulating transcription, regulating R-loops, modulating the chromatin, regulating cell cycle, enforcing checkpoints, maintaining telomeres, and in transcription-coupled repair [ 17 , 35 , 36 , 37 ]. Most recently, Hatchi and colleagues reported that a species of single-stranded DNA damage-associated small RNAs (sdRNA), generated by a BRCA1 -RNAi complex, promote DNA repair mediated by PALB2-RAD52 complex at R-loop-forming transcriptional termination pause sites [ 38 ].…”

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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BRCA1 and RNAi factors promote repair mediated by small RNAs and PALB2–RAD52

Cited by 33 publications

References 53 publications

Disruption of a ∼23–24 nucleotide small RNA pathway elevates DNA damage responses in Tetrahymena thermophila

Disruption of a ∼23–24 nucleotide small RNA pathway elevates DNA damage responses in Tetrahymena thermophila

Home and Away: The Role of Non-Coding RNA in Intracellular and Intercellular DNA Damage Response

BRCA1 and Metastasis: Outcome of Defective DNA Repair

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