Nonsense-mediated decay regulates key components of homologous recombination

Janke, Ryan; Kong, Jeremy; Braberg, Hannes; Cantin, Greg T.; Yates, John R.; Krogan, Nevan J.; Heyer, Wolf Dietrich

doi:10.1093/nar/gkw182

Cited by 18 publications

(19 citation statements)

References 82 publications

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“…SMG-1 is absolutely required for NMD in C. elegans ( Hodgkin et al 1989 ), and the fact that we observe the same IR sensitivity phenotype in all NMD mutants of the NMD pathway we examined supports this hypothesis. This hypothesis is in line with recent observations made in the budding yeast system where it was shown that the levels of RAD55, RAD51, RAD54, and RAD57 recombination proteins were regulated by NMD ( Janke et al 2016 ). These authors did not report sensitivity to IR, but found that affected mutants are resistant to MMS.…”

Section: Discussionsupporting

confidence: 92%

A Role for the Nonsense-Mediated mRNA Decay Pathway in Maintaining Genome Stability in Caenorhabditis elegans

2017

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Ionizing radiation (IR) is commonly used in cancer therapy and is a main source of DNA double-strand breaks (DSBs), one of the most toxic forms of DNA damage. We have used Caenorhabditis elegans as an invertebrate model to identify novel factors required for repair of DNA damage inflicted by IR. We have performed an unbiased genetic screen, finding that smg-1 mutations confer strong hyper-sensitivity to IR. SMG-1 is a phosphoinositide-3 kinase (PI3K) involved in mediating nonsense-mediated mRNA decay (NMD) of transcripts containing premature stop codons and related to the ATM and ATR kinases which are at the apex of DNA damage signaling pathways. Hyper-sensitivity to IR also occurs when other genes mediating NMD are mutated. The hyper-sensitivity to bleomycin, a drug known to induce DSBs, further supports that NMD pathway mutants are defective in DSB repair. Hyper-sensitivity was not observed upon treatment with alkylating agents or UV irradiation. We show that SMG-1 mainly acts in mitotically dividing germ cells, and during late embryonic and larval development. Based on epistasis experiments, SMG-1 does not appear to act in any of the three major pathways known to mend DNA DSBs, namely homologous recombination (HR), nonhomologous end-joining (NHEJ), and microhomology-mediated end-joining (MMEJ). We speculate that SMG-1 kinase activity could be activated following DNA damage to phosphorylate specific DNA repair proteins and/or that NMD inactivation may lead to aberrant mRNAs leading to synthesis of malfunctioning DNA repair proteins.

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Section: Discussionsupporting

confidence: 92%

A Role for the Nonsense-Mediated mRNA Decay Pathway in Maintaining Genome Stability in Caenorhabditis elegans

2017

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“…Deletion of NMD and mating-type silencing made both rad53 ∆ and RAD53 cells more resistant to DNA damage, and were therefore not characterized in detail (Figure 5 and Figure 6; Haber 2012). Loss of NMD has been shown to upregulate the levels of several proteins involved in homologous recombination and increase recombination rates (Janke et al 2016), which could explain the suppression we have seen. Although the exact molecular mechanism by which MAT heterozygosity confers more resistance to DNA damage is unknown, some aspects of DNA repair are known to be under mating-type control; for example, nonhomologous end joining is repressed and spontaneous recombination is enhanced in MAT a /α cells [reviewed in Haber (2012)].…”

Section: Discussionmentioning

confidence: 80%

Rpd3L Contributes to the DNA Damage Sensitivity ofSaccharomyces cerevisiaeCheckpoint Mutants

et al. 2018

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DNA replication forks that are stalled by DNA damage activate an S-phase checkpoint that prevents irreversible fork arrest and cell death. The increased cell death caused by DNA damage in budding yeast cells lacking the Rad53 checkpoint protein kinase is partially suppressed by deletion of the EXO1 gene. Using a whole-genome sequencing approach, we identified two additional genes, RXT2 and RPH1, whose mutation can also partially suppress this DNA damage sensitivity. We provide evidence that RXT2 and RPH1 act in a common pathway, which is distinct from the EXO1 pathway. Analysis of additional mutants indicates that suppression works through the loss of the Rpd3L histone deacetylase complex. Our results suggest that the loss or absence of histone acetylation, perhaps at stalled forks, may contribute to cell death in the absence of a functional checkpoint.

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“…Factors involved in RNA metabolism play also more direct roles in the DDR by either recruiting DDR proteins to the site of damage or regulating the expression of repair and checkpoint genes at different levels ( 11 ). Finally, the conserved nonsense-mediated decay (NMD) pathway was recently found to limit HR in S. cerevisiae undamaged cells by controlling the transcript and protein levels of HR factors ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

The RNA binding protein Npl3 promotes resection of DNA double-strand breaks by regulating the levels of Exo1

Colombo

Trovesi

Menin

et al. 2017

Nucleic Acids Research

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Eukaryotic cells preserve genome integrity upon DNA damage by activating a signaling network that promotes DNA repair and controls cell cycle progression. One of the most severe DNA damage is the DNA double-strand break (DSB), whose 5΄ ends can be nucleolitically resected by multiple nucleases to create 3΄-ended single-stranded DNA tails that trigger DSB repair by homologous recombination. Here, we identify the Saccharomyces cerevisiae RNA binding protein Npl3 as a new player in DSB resection. Npl3 is related to both the metazoan serine-arginine-rich and the heterogeneous nuclear ribonucleo-proteins. NPL3 deletion impairs the generation of long ssDNA tails at the DSB ends, whereas it does not exacerbate the resection defect of exo1Δ cells. Furthermore, either the lack of Npl3 or the inactivation of its RNA-binding domains causes decrease of the exonuclease Exo1 protein levels as well as generation of unusual and extended EXO1 RNA species. These findings, together with the observation that EXO1 overexpression partially suppresses the resection defect of npl3Δ cells, indicate that Npl3 participates in DSB resection by promoting the proper biogenesis of EXO1 mRNA.

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Nonsense-mediated decay regulates key components of homologous recombination

Cited by 18 publications

References 82 publications

A Role for the Nonsense-Mediated mRNA Decay Pathway in Maintaining Genome Stability in Caenorhabditis elegans

A Role for the Nonsense-Mediated mRNA Decay Pathway in Maintaining Genome Stability in Caenorhabditis elegans

Rpd3L Contributes to the DNA Damage Sensitivity ofSaccharomyces cerevisiaeCheckpoint Mutants

The RNA binding protein Npl3 promotes resection of DNA double-strand breaks by regulating the levels of Exo1

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