lncRNA HOTAIRM1 Coordinates with RNA Processing Factors in DNA Damage Repair

The eukaryotic RNA processing factor Y14 participates in double-strand break (DSB) repair via its RNA-dependent interaction with the non-homologous end-joining (NHEJ) complex. We identified the long non-coding RNA HOTAIRM1 as a candidate that mediates this interaction. HOTAIRM1 localized to DNA damage sites induced by ionizing radiation. Depletion of HOTAIRM1 delayed the recruitment of DNA damage response and repair factors to DNA lesions and reduced DNA repair efficiency. Identification of the HOTAIRM1 interactome revealed a large set of RNA processing factors including mRNA surveillance factors. The surveillance factors Upf1 and SMG6 localized to DNA damage sites in a HOTAIRM1-dependent manner. Depletion of Upf1 or SMG6 increased the level of DSB-induced non-coding transcripts at damaged sites, indicating a pivotal role for Upf1/SMG6-mediated RNA degradation in DNA repair. We conclude that HOTAIRM1 serves as an assembly scaffold for both DNA repair and RNA processing factors that act in concert to repair DSBs.

[1]  J. Zucman‐Rossi,et al.  Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma , 2021, Cancer Research.

[2]  D. Baird,et al.  UPF1 promotes the formation of R loops to stimulate DNA double-strand break repair , 2021, Nature Communications.

[3]  Stéphanie Panier,et al.  New Faces of old Friends: Emerging new Roles of RNA-Binding Proteins in the DNA Double-Strand Break Response , 2021, Frontiers in Molecular Biosciences.

[4]  Juan Shi,et al.  H. pylori infection alters repair of DNA double-strand breaks via SNHG17. , 2020, The Journal of clinical investigation.

[5]  T. Blundell,et al.  Mechanism of efficient double-strand break repair by a long non-coding RNA , 2020, Nucleic acids research.

[6]  Tiziana Santini,et al.  HOTAIRM1 regulates neuronal differentiation by modulating NEUROGENIN 2 and the downstream neurogenic cascade , 2020, Cell Death & Disease.

[7]  C. Peng,et al.  BGL3 lncRNA mediates retention of the BRCA1/BARD1 complex at DNA damage sites , 2020, The EMBO journal.

[8]  N. Visa,et al.  RNA at DNA Double‐Strand Breaks: The Challenge of Dealing with DNA:RNA Hybrids , 2020, BioEssays : news and reviews in molecular, cellular and developmental biology.

[9]  P. Libby,et al.  Long noncoding RNA SNHG12 integrates a DNA-PK–mediated DNA damage response and vascular senescence , 2020, Science Translational Medicine.

[10]  F. d’Adda di Fagagna,et al.  Functional transcription promoters at DNA double-strand breaks mediate RNA-driven phase separation of damage response factors , 2019, Nature Cell Biology.

[11]  L. Maquat,et al.  Quality and quantity control of gene expression by nonsense-mediated mRNA decay , 2019, Nature Reviews Molecular Cell Biology.

[12]  Jing Wang,et al.  WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs , 2019, Nucleic Acids Res..

[13]  M. Friedländer,et al.  EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks , 2019, Nature Communications.

[14]  W. Tarn,et al.  The RNA Processing Factor Y14 Participates in DNA Damage Response and Repair , 2019, iScience.

[15]  A. Venkitaraman,et al.  BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment , 2018, Nature Communications.

[16]  Lennart Martens,et al.  LNCipedia 5: towards a reference set of human long non-coding RNAs , 2018, Nucleic Acids Res..

[17]  Jiahua Yu,et al.  Quantitative assessment of HR and NHEJ activities via CRISPR/Cas9-induced oligodeoxynucleotide-mediated DSB repair. , 2018, DNA repair.

[18]  Jacob C. Ulirsch,et al.  The NORAD lncRNA assembles a topoisomerase complex critical for genome stability , 2018, Nature.

[19]  E. Benarroch,et al.  DNA damage response , 2018, Neurology.

[20]  G. Legube,et al.  Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations , 2018, Nature Communications.

[21]  G. Shivashankar,et al.  Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks , 2017, Nature Cell Biology.

[22]  Yuming Wang,et al.  Studies of lncRNAs in DNA double strand break repair: what is new? , 2017, Oncotarget.

[23]  W. Tarn,et al.  Y14 governs p53 expression and modulates DNA damage sensitivity , 2017, Scientific Reports.

[24]  A. Porcellini,et al.  Non-homologous end joining induced alterations in DNA methylation: A source of permanent epigenetic change , 2017, Oncotarget.

[25]  M. Bushell,et al.  The emerging role of RNAs in DNA damage repair , 2017, Cell Death and Differentiation.

[26]  Zhentian Li,et al.  SFPQ•NONO and XLF function separately and together to promote DNA double-strand break repair via canonical nonhomologous end joining , 2016, Nucleic acids research.

[27]  Yasutake Katoh,et al.  Ubiquitylation of Ku80 by RNF126 Promotes Completion of Nonhomologous End Joining-Mediated DNA Repair , 2016, Molecular and Cellular Biology.

[28]  F. Setién,et al.  Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer , 2016, Proceedings of the National Academy of Sciences.

[29]  A. Chakraborty,et al.  Classical non-homologous end-joining pathway utilizes nascent RNA for error-free double-strand break repair of transcribed genes , 2016, Nature Communications.

[30]  Howard Y. Chang,et al.  An inducible long noncoding RNA amplifies DNA damage signaling , 2016, Nature Genetics.

[31]  K. Nakai,et al.  The Exon Junction Complex Controls the Efficient and Faithful Splicing of a Subset of Transcripts Involved in Mitotic Cell-Cycle Progression , 2016, International journal of molecular sciences.

[32]  K. Mahajan,et al.  hPso4/hPrp19: a critical component of DNA repair and DNA damage checkpoint complexes , 2016, Oncogene.

[33]  Mihoko Kai.  Roles of RNA-Binding Proteins in DNA Damage Response , 2016, International journal of molecular sciences.

[34]  Y. Lou,et al.  A Point Mutation in the Exon Junction Complex Factor Y14 Disrupts Its Function in mRNA Cap Binding and Translation Enhancement* , 2016, The Journal of Biological Chemistry.

[35]  Tsung-Cheng Chang,et al.  Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins , 2016, Cell.

[36]  David J. Chen,et al.  Phosphorylation of Ku dictates DNA double-strand break (DSB) repair pathway choice in S phase , 2015, Nucleic acids research.

[37]  Tom Misteli,et al.  A BRCA1‐interacting lncRNA regulates homologous recombination , 2015, EMBO reports.

[38]  J. Lukas,et al.  Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose) , 2015, Nature Communications.

[39]  A. Conesa,et al.  Data quality aware analysis of differential expression in RNA-seq with NOISeq R/Bioc package , 2015, Nucleic acids research.

[40]  S. Jackson,et al.  Neddylation Promotes Ubiquitylation and Release of Ku from DNA-Damage Sites , 2015, Cell reports.

[41]  M. Tsai,et al.  PHRF1 promotes genome integrity by modulating non-homologous end-joining , 2015, Cell Death and Disease.

[42]  N. Visa,et al.  RRP6/EXOSC10 is required for the repair of DNA double-strand breaks by homologous recombination , 2015, Journal of Cell Science.

[43]  Martin J. Aryee,et al.  GUIDE-Seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases , 2014, Nature Biotechnology.

[44]  A. Sandelin,et al.  Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes , 2014, Genes & development.

[45]  J. Ule,et al.  3' UTR length and messenger ribonucleoprotein composition determine endocleavage efficiencies at termination codons. , 2014, Cell reports.

[46]  C. Delteil,et al.  DNA damage triggers SAF-A and RNA biogenesis factors exclusion from chromatin coupled to R-loops removal , 2014, Nucleic acids research.

[47]  F. Bonneau,et al.  Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5–SMG7 and SMG6 , 2014, Nucleic acids research.

[48]  M. Salto‐Tellez,et al.  Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability , 2014, Molecular cell.

[49]  L. Zou,et al.  PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. , 2014, Molecular cell.

[50]  Majid Hafezparast,et al.  PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage , 2013, Nucleic acids research.

[51]  Piero Carninci,et al.  Site-specific DICER and DROSHA RNA products control the DNA damage response , 2012, Nature.

[52]  David R. Kelley,et al.  Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks , 2012, Nature Protocols.

[53]  Sherif Abou Elela,et al.  Proteins Associated with the Exon Junction Complex Also Control the Alternative Splicing of Apoptotic Regulators , 2011, Molecular and Cellular Biology.

[54]  F. Hirahara,et al.  N- and C-terminal Upf1 phosphorylations create binding platforms for SMG-6 and SMG-5:SMG-7 during NMD , 2011, Nucleic acids research.

[55]  M. Lieber,et al.  The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. , 2010, Annual review of biochemistry.

[56]  C. Walsh,et al.  The exon junction complex component Magoh controls brain size by regulating neural stem cell division , 2010, Nature Neuroscience.

[57]  J. Bartek,et al.  The DNA-damage response in human biology and disease , 2009, Nature.

[58]  H. Kurumizaka,et al.  Human PSF binds to RAD51 and modulates its homologous-pairing and strand-exchange activities , 2009, Nucleic acids research.

[59]  C. Glass,et al.  Induced ncRNAs Allosterically Modify RNA Binding Proteins in cis to Inhibit Transcription , 2008, Nature.

[60]  E. Conti,et al.  Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex , 2006, The EMBO journal.

[61]  C. Azzalin,et al.  The Human RNA Surveillance Factor UPF1 Is Required for S Phase Progression and Genome Stability , 2006, Current Biology.

[62]  W. Tarn,et al.  Phosphorylation of Y14 Modulates Its Interaction with Proteins Involved in mRNA Metabolism and Influences Its Methylation* , 2005, Journal of Biological Chemistry.

[63]  B. Snow,et al.  Functional Conservation of the Telomerase Protein Est1p in Humans , 2003, Current Biology.

[64]  P. Bucher,et al.  A Human Homolog of Yeast Est1 Associates with Telomerase and Uncaps Chromosome Ends When Overexpressed , 2003, Current Biology.