@article{%a1.%Yb_47,

title = {TGS1 impacts snRNA 3'-end processing, ameliorates survival motor neuron-dependent neurological phenotypes in vivo and prevents neurodegeneration},

author = {Chen L and Roake CM and Maccallini P and Bavasso F and Dehghannasiri R and Santonicola P and Mendoza-Ferreira N and Scatolini L and Rizzuti L and Esposito A and Gallotta I and Francia S and Cacchione S and Galati A and Palumbo V and Kobin MA and Tartaglia GG and Colantoni A and Proietti G and Wu Y and Hammerschmidt M and De Pittà C and Sales G and Salzman J and Pellizzoni L and Wirth B and Schiavi ED and Gatti M and Artandi SE and Raffa GD},

url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkac659/6659874?login=true},

doi = {10.1093/nar/gkac659},

year  = {2022},

date = {2022-03-31},

journal = {Nucleic acids research},

volume = {50},

number = {12400},

issue = {21},

pages = {12424},

abstract = {Trimethylguanosine synthase 1 (TGS1) is a highly conserved enzyme that converts the 5'-monomethylguanosine cap of small nuclear RNAs (snRNAs) to a trimethylguanosine cap. Here, we show that loss of TGS1 in Caenorhabditis elegans, Drosophila melanogaster and Danio rerio results in neurological phenotypes similar to those caused by survival motor neuron (SMN) deficiency. Importantly, expression of human TGS1 ameliorates the SMN-dependent neurological phenotypes in both flies and worms, revealing that TGS1 can partly counteract the effects of SMN deficiency. TGS1 loss in HeLa cells leads to the accumulation of immature U2 and U4atac snRNAs with long 3' tails that are often uridylated. snRNAs with defective 3' terminations also accumulate in Drosophila Tgs1 mutants. Consistent with defective snRNA maturation, TGS1 and SMN mutant cells also exhibit partially overlapping transcriptome alterations that include aberrantly spliced and readthrough transcripts. Together, these results identify a neuroprotective function for TGS1 and reinforce the view that defective snRNA maturation affects neuronal viability and function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_131,

title = {A Role for Human DNA Polymerase lambda in Alternative Lengthening of Telomeres},

author = {Mentegari E and Bertoletti F and Kissova M and Zucca E and Galli S and Tagliavini G and Garbelli A and Maffia A and Bione S and Ferrari E and {d'Adda di Fagagna F} and Francia S and Sabbioneda S and Chen LY and Lingner J and Bergoglio V and Hoffmann JS and Hubscher U and Crespan E and Maga G},

url = {https://www.mdpi.com/1422-0067/22/5/2365},

doi = {10.3390/ijms22052365},

year  = {2021},

date = {2021-03-09},

journal = {International journal of molecular sciences},

volume = {22},

number = {5},

pages = {2365},

abstract = {Telomerase negative cancer cell types use the Alternative Lengthening of Telomeres (ALT) pathway to elongate telomeres ends. Here, we show that silencing human DNA polymerase (Pol lambda) in ALT cells represses ALT activity and induces telomeric stress. In addition, replication stress in the absence of Pol lambda, strongly affects the survival of ALT cells. In vitro, Pol lambda can promote annealing of even a single G-rich telomeric repeat to its complementary strand and use it to prime DNA synthesis. The noncoding telomeric repeat containing RNA TERRA and replication protein A negatively regulate this activity, while the Protection of Telomeres protein 1 (POT1)/TPP1 heterodimer stimulates Pol lambda. Pol lambda associates with telomeres and colocalizes with TPP1 in cells. In summary, our data suggest a role of Pol lambda in the maintenance of telomeres by the ALT mechanism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_465,

title = {DNA Damage Triggers a New Phase in Neurodegeneration},

author = {Pessina F and Gioia U and Brandi O and Farina S and Ceccon M and Francia S and {d'Adda di Fagagna F}},

url = {https://www.sciencedirect.com/science/article/pii/S0168952520302420?via%3Dihub},

doi = {10.1016/j.tig.2020.09.006},

year  = {2021},

date = {2021-03-03},

journal = {Trends in genetics },

volume = {37},

number = {4},

pages = {337-354},

abstract = {Subcellular compartmentalization contributes to the organization of a plethora of molecular events occurring within cells. This can be achieved in membraneless organelles generated through liquid-liquid phase separation (LLPS), a demixing process that separates and concentrates cellular reactions. RNA is often a critical factor in mediating LLPS. Recent evidence indicates that DNA damage response foci are membraneless structures formed via LLPS and modulated by noncoding transcripts synthesized at DNA damage sites. Neurodegeneration is often associated with DNA damage, and dysfunctional LLPS events can lead to the formation of toxic aggregates. In this review, we discuss those gene products involved in neurodegeneration that undergo LLPS and their involvement in the DNA damage response.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y__491,

title = {DROSHA is recruited to DNA damage sites by the MRN complex to promote non-homologous end-joining},

author = {Cabrini M and Roncador M and Galbiati A and Cipolla L and Maffia A and Iannelli F and Sabbioneda S and {d'Adda di Fagagna F} and Francia S},

url = {https://jcs.biologists.org/content/early/2021/02/04/jcs.249706.long},

doi = {10.1242/jcs.249706},

year  = {2021},

date = {2021-03-09},

journal = {Journal of cell science},

volume = {134},

number = {6},

pages = {jcs249706},

abstract = {The DNA damage response (DDR) is the signaling cascade that recognizes DNA double-strand breaks (DSB) and promotes their resolution via the DNA repair pathways of Non-Homologous End Joining (NHEJ) or Homologous Recombination (HR). We and others have shown that DDR activation requires DROSHA. However, whether DROSHA exerts its functions by associating with damage sites, what controls its recruitment and how DROSHA influences DNA repair, remains poorly understood. Here we show that DROSHA associates to DSBs independently from transcription. Neither H2AX, nor ATM nor DNA-PK kinase activities are required for its recruitment to break site. Rather, DROSHA interacts with RAD50 and inhibition of MRN by Mirin treatment abolishes this interaction. MRN inactivation by RAD50 knockdown or mirin treatment prevents DROSHA recruitment to DSB and, as a consequence, also 53BP1 recruitment. During DNA repair, DROSHA inactivation reduces NHEJ and boosts HR frequency. Indeed, DROSHA knockdown also increase the association of downstream HR factors such as RAD51 to DNA ends. Overall, our results demonstrate that DROSHA is recruited at DSBs by the MRN complex and direct DNA repair toward NHEJ.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y__503,

title = {MRE11-RAD50-NBS1 Complex Is Sufficient to Promote Transcription by RNA Polymerase II at Double-Strand Breaks by Melting DNA Ends. },

author = {Sharma S and Anand R and Zhang X and Francia S and Michelini F and Galbiati A and Williams H and Ronato DA and Masson JY and Rothenberg E and Cejka P and {d'Adda di Fagagna F}},

url = {https://www.cell.com/cell-reports/fulltext/S2211-1247(20)31554-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124720315540%3Fshowall%3Dtrue},

doi = {10.1016/j.celrep.2020.108565},

year  = {2021},

date = {2021-03-09},

journal = {Cell reports},

volume = {34},

number = {1},

pages = {108565},

abstract = {The MRE11-RAD50-NBS1 (MRN) complex supports the synthesis of damage-induced long non-coding RNA (dilncRNA) by RNA polymerase II (RNAPII) from DNA double-strand breaks (DSBs) by an unknown mechanism. Here, we show that recombinant human MRN and native RNAPII are sufficient to reconstitute a minimal functional transcriptional apparatus at DSBs. MRN recruits and stabilizes RNAPII at DSBs. Unexpectedly, transcription is promoted independently from MRN nuclease activities. Rather, transcription depends on the ability of MRN to melt DNA ends, as shown by the use of MRN mutants and specific allosteric inhibitors. Single-molecule FRET assays with wild-type and mutant MRN show a tight correlation between the ability to melt DNA ends and to promote transcription. The addition of RPA enhances MRN-mediated transcription, and unpaired DNA ends allow MRN-independent transcription by RNAPII. These results support a model in which MRN generates single-strand DNA ends that favor the initiation of transcription by RNAPII.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Ybv,

title = {Post-Translational Modifications Modulate Proteinopathies of TDP-43, FUS and hnRNP-A/B in Amyotrophic Lateral Sclerosis. },

author = {Farina S and Esposito F and Battistoni M and Biamonti G and Francia S},

url = {https://www.frontiersin.org/articles/10.3389/fmolb.2021.693325/full},

doi = {10.3389/fmolb.2021.693325},

year  = {2021},

date = {2021-08-25},

journal = {Frontiers in molecular biosciences},

volume = {8},

abstract = {It has been shown that protein low-sequence complexity domains (LCDs) induce liquid-liquid phase separation (LLPS), which is responsible for the formation of membrane-less organelles including P-granules, stress granules and Cajal bodies. Proteins harbouring LCDs are widely represented among RNA binding proteins often mutated in ALS. Indeed, LCDs predispose proteins to a prion-like behaviour due to their tendency to form amyloid-like structures typical of proteinopathies. Protein post-translational modifications (PTMs) can influence phase transition through two main events: i) destabilizing or augmenting multivalent interactions between phase-separating macromolecules; ii) recruiting or excluding other proteins and/or nucleic acids into/from the condensate. In this manuscript we summarize the existing evidence describing how PTM can modulate LLPS thus favouring or counteracting proteinopathies at the base of neurodegeneration in ALS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%_38,

title = {Pharmacological boost of DNA damage response and repair by enhanced biogenesis of DNA damage response RNAs.},

author = {Gioia U and Francia S and Cabrini M and Brambillasca S and Michelini F and Jones-Weinert CW and {d'Adda di Fagagna F}},

url = {https://www.nature.com/articles/s41598-019-42892-6},

doi = {10.1038/s41598-019-42892-6},

year  = {2019},

date = {2019-04-23},

journal = {Scientific reports},

volume = {9},

number = {1},

pages = {6460},

abstract = {A novel class of small non-coding RNAs called DNA damage response RNAs (DDRNAs) generated at DNA double-strand breaks (DSBs) in a DROSHA- and DICER-dependent manner has been shown to regulate the DNA damage response (DDR). Similar molecules were also reported to guide DNA repair. Here, we show that DDR activation and DNA repair can be pharmacologically boosted by acting on such non-coding RNAs. Cells treated with enoxacin, a compound previously demonstrated to augment DICER activity, show stronger DDR signalling and faster DNA repair upon exposure to ionizing radiations compared to vehicle-only treated cells. Enoxacin stimulates DDRNA production at chromosomal DSBs and at dysfunctional telomeres, which in turn promotes 53BP1 accumulation at damaged sites, therefore in a miRNA-independent manner. Increased 53BP1 occupancy at DNA lesions induced by enoxacin ultimately suppresses homologous recombination, channelling DNA repair towards faster and more accurate non-homologous end-joining, including in post-mitotic primary neurons. Notably, augmented DNA repair stimulated by enoxacin increases the survival also of cancer cells treated with chemotherapeutic agents.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_72,

title = {RNase A treatment and reconstitution with DNA damage response RNA in living cells as a tool to study the role of non-coding RNA in the formation of DNA damage response foci.},

author = {Michelini F and Rossiello F and {d'Adda di Fagagna F} and Francia S},

url = {https://www.nature.com/articles/s41596-019-0147-5},

doi = {https://www.nature.com/articles/s41596-019-0147-5},

year  = {2019},

date = {2019-05-17},

journal = {Nature protocols},

volume = {14},

number = {5},

pages = {1489-1508},

abstract = {Non-coding RNA (ncRNA) molecules have been shown to play a variety of cellular roles; however, the contributions of different types of RNA to specific phenomena are often hard to dissect. To study the role of RNA in the assembly of DNA damage response (DDR) foci, we developed the RNase A treatment and reconstitution (RATaR) method, in which cells are mildly permeabilized, incubated with recombinant RNase A and subsequently reconstituted with different RNA species, under conditions of RNase A inactivation and inhibition of endogenous transcription. The block of transcription right after RNase A removal represents a key innovation of RATaR, preventing potential contributions of endogenously neo-synthesized transcripts to the phenotypes studied. A critical aspect of this technique is the balance between sufficient permeabilization of membranes to allow enzyme/RNA access into the cell nucleus and cell viability. Here, we present our protocol for RNA-dependent DDR foci disassembly and reassembly using fluorescent DDR RNAs (DDRNAs) in NIH2/4 cells, an engineered NIH3T3-derived cell line. The use of sequence-specific, fluorescent RNA molecules permits the concomitant determination of their subcellular localization and biological functions. We also outline adaptations of RATaR when implemented in different cell lines exposed to various genotoxic treatments, such as γ-radiation, restriction enzymes and telomere deprotection. In all these cases, the entire procedure can be completed within 2 h without the need for special equipment or uncommon skills. We believe this technique will prove useful for investigating the contribution of RNA to a variety of relevant cellular processes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_161,

title = {From "Cellular" RNA to "Smart" RNA: Multiple Roles of RNA in Genome Stability and Beyond.},

author = {Michelini F and Jalihal AP and Francia S and Meers C and Neeb ZT and Rossiello F and Gioia U and Aguado J and Jones-Weinert C and Luke B and Biamonti G and Nowacki M and Storici F and Carninci P and Walter NG and {d'Adda di Fagagna F}},

url = {https://pubs.acs.org/doi/10.1021/acs.chemrev.7b00487},

doi = {10.1021/acs.chemrev.7b00487},

year  = {2018},

date = {2018-04-25},

journal = {Chemical reviews},

volume = {118},

number = {8},

pages = {4365-4403},

abstract = {Coding for proteins has been considered the main function of RNA since the "central dogma" of biology was proposed. The discovery of noncoding transcripts shed light on additional roles of RNA, ranging from the support of polypeptide synthesis, to the assembly of subnuclear structures, to gene expression modulation. Cellular RNA has therefore been recognized as a central player in often unanticipated biological processes, including genomic stability. This ever-expanding list of functions inspired us to think of RNA as a "smart" phone, which has replaced the older obsolete "cellular" phone. In this review, we summarize the last two decades of advances in research on the interface between RNA biology and genome stability. We start with an account of the emergence of noncoding RNA, and then we discuss the involvement of RNA in DNA damage signaling and repair, telomere maintenance, and genomic rearrangements. We continue with the depiction of single-molecule RNA detection techniques, and we conclude by illustrating the possibilities of RNA modulation in hopes of creating or improving new therapies. The widespread biological functions of RNA have made this molecule a reoccurring theme in basic and translational research, warranting it the transcendence from classically studied "cellular" RNA to "smart" RNA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_185,

title = {A damaged genome’s transcriptional landscape through multilayered expression profiling around in situ-mapped DNA double-strand breaks},

author = {Iannelli F and Galbiati A and Capozzo I and Nguyen Q and Magnuson B and Michelini F and D'Alessandro G and Cabrini M and Roncador M and Francia S and Crosetto N and Ljungman M and Carninci P and {d'Adda di Fagagna F}},

url = {https://www.nature.com/articles/ncomms15656},

doi = {10.1038/ncomms15656},

year  = {2017},

date = {2017-02-23},

journal = {Nature Communications},

volume = {8},

pages = {15656},

abstract = {Of the many types of DNA damage, DNA double-strand breaks (DSBs) are probably the most deleterious. Mounting evidence points to an intricate relationship between DSBs and transcription. A cell system in which the impact on transcription can be investigated at precisely mapped genomic DSBs is essential to study this relationship. Here in a human cell line, we map genome-wide and at high resolution the DSBs induced by a restriction enzyme, and we characterize their impact on gene expression by four independent approaches by monitoring steady-state RNA levels, rates of RNA synthesis, transcription initiation and RNA polymerase II elongation. We consistently observe transcriptional repression in proximity to DSBs. Downregulation of transcription depends on ATM kinase activity and on the distance from the DSB. Our study couples for the first time, to the best of our knowledge, high-resolution mapping of DSBs with multilayered transcriptomics to dissect the events shaping gene expression after DSB induction at multiple endogenous sites.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_214,

title = {A missense MT-ND5 mutation in differentiated Parkinson Disease cytoplasmic hybrid induces ROS-dependent DNA Damage Response amplified by DROSHA.},

author = {Pignataro D and Francia S and Zanetta F and Brenna G and Brandini S and Olivieri A and Torroni A and Biamonti G and Montecucco A},

url = {https://www.nature.com/articles/s41598-017-09910-x},

doi = {10.1038/s41598-017-09910-x},

year  = {2017},

date = {2017-02-22},

journal = {Scientific reports},

volume = {7},

number = {1},

pages = {9528},

abstract = {Genome integrity is continuously threatened by endogenous sources of DNA damage including reactive oxygen species (ROS) produced by cell metabolism. Factors of the RNA interference (RNAi) machinery have been recently involved in the cellular response to DNA damage (DDR) in proliferating cells. To investigate the impact of component of RNAi machinery on DDR activation in terminally differentiated cells, we exploited cytoplasmic hybrid (cybrid) cell lines in which mitochondria of sporadic Parkinson's disease patients repopulate neuroblastoma SH-SY5Y-Rho(0) cells. Upon differentiation into dopaminergic neuron-like cells, PD63 cybrid showed increased intracellular level of ROS and chronic DDR activation, compared to other cybrids with the same nuclear background. Importantly, DDR activation in these cells can be prevented by ROS scavenging treatment suggesting that ROS production is indeed causative of nuclear DNA damage. Sequence analysis of the mitogenomes identified a rare and heteroplasmic missense mutation affecting a highly conserved residue of the ND5-subunit of respiratory complex I, which accounts for ROS increase. We demonstrated that the assembly of nuclear DDR foci elicited by oxidative stress in these cells relies on DROSHA, providing the first evidence that components of RNAi machinery play a crucial role also in the mounting of ROS-induced DDR in non-replicating neuronal cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_184,

title = {Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks},

author = {Michelini F and Pitchiaya S and Vitelli V and Sharma S and Gioia U and Pessina F and Cabrini M and Wang Y and Capozzo I and Iannelli F and Matti V and Francia S and Shivashankar GV and Walter NG and {d'Adda di Fagagna F}},

url = {https://www.nature.com/articles/ncb3643},

doi = {10.1038/ncb3643},

year  = {2017},

date = {2017-02-22},

journal = {Nature cell biology},

volume = {19},

issue = {12},

pages = {1400-1410},

abstract = {The DNA damage response (DDR) preserves genomic integrity. Small non-coding RNAs termed DDRNAs are generated at DNA double-strand breaks (DSBs) and are critical for DDR activation. Here we show that active DDRNAs specifically localize to their damaged homologous genomic sites in a transcription-dependent manner. Following DNA damage, RNA polymerase II (RNAPII) binds to the MRE11-RAD50-NBS1 complex, is recruited to DSBs and synthesizes damage-induced long non-coding RNAs (dilncRNAs) from and towards DNA ends. DilncRNAs act both as DDRNA precursors and by recruiting DDRNAs through RNA-RNA pairing. Together, dilncRNAs and DDRNAs fuel DDR focus formation and associate with 53BP1. Accordingly, inhibition of RNAPII prevents DDRNA recruitment, DDR activation and DNA repair. Antisense oligonucleotides matching dilncRNAs and DDRNAs impair site-specific DDR focus formation and DNA repair. We propose that DDR signalling sites, in addition to sharing a common pool of proteins, individually host a unique set of site-specific RNAs necessary for DDR activation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_322,

title = {Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks.},

author = {Michelini F and Pitchiaya S and Vitelli V and Sharma S and Gioia U and Pessina F and Cabrini M and Wang Y and Capozzo I and Iannelli F and Matti V and Francia S and Shivashankar GV and Walter NG and {d'Adda di Fagagna F}},

url = {https://www.nature.com/articles/ncb3643},

doi = {10.1038/ncb3643},

year  = {2017},

date = {2017-02-28},

journal = {Nature cell biology},

volume = {19},

number = {2},

pages = {1400-1410},

abstract = {The DNA damage response (DDR) preserves genomic integrity. Small non-coding RNAs termed DDRNAs are generated at DNA double-strand breaks (DSBs) and are critical for DDR activation. Here we show that active DDRNAs specifically localize to their damaged homologous genomic sites in a transcription-dependent manner. Following DNA damage, RNA polymerase II (RNAPII) binds to the MRE11-RAD50-NBS1 complex, is recruited to DSBs and synthesizes damage-induced long non-coding RNAs (dilncRNAs) from and towards DNA ends. DilncRNAs act both as DDRNA precursors and by recruiting DDRNAs through RNA-RNA pairing. Together, dilncRNAs and DDRNAs fuel DDR focus formation and associate with 53BP1. Accordingly, inhibition of RNAPII prevents DDRNA recruitment, DDR activation and DNA repair. Antisense oligonucleotides matching dilncRNAs and DDRNAs impair site-specific DDR focus formation and DNA repair. We propose that DDR signalling sites, in addition to sharing a common pool of proteins, individually host a unique set of site-specific RNAs necessary for DDR activation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_210,

title = {Express or Repress? The Transcriptional Dilemma of Damaged Chromatin.},

author = {Capozzo I and Iannelli F and Francia S and {d'Adda di Fagagna F}},

url = {http://onlinelibrary.wiley.com/doi/10.1111/febs.14048/abstract},

doi = {10.1111/febs.14048},

year  = {2017},

date = {2017-02-15},

journal = {FEBS journal},

volume = {284},

number = {14},

pages = {2133-2147},

abstract = {The fine modulation of transcriptional activity around DNA lesions is essential to carefully regulate the crosstalk between transcription, the DNA damage response, and DNA repair, particularly when the lesion occurs next to, or within, actively transcribed genes. Recently, several studies have been carried out to investigate how DNA lesions have an impact on local transcription, but the emerging model remains incomplete. Transcription of genes around damaged DNA is actively down-regulated by the DNA damage response through different mechanisms, which appear specific to the chromatin context, the type of DNA damage or its complexity. Intriguingly, emerging evidence also indicates that transcription of non-coding RNAs (ncRNAs) is induced at sites of DNA damage, producing small ncRNAs that are, in turn, required for a full DDR activation. We discuss here these recent findings, highlighting the major unresolved questions in the field, and propose ways to reconcile these apparently contradictory observations. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_216,

title = {Transcriptional and post-transcriptional regulation of the ionizing radiation response by ATM and p53.},

author = {Venkata Narayanan I and Paulsen MT and Bedi K and Berg N and Ljungman EA and Francia S and Veloso A and Magnuson B and {d'Adda di Fagagna F} and Wilson TE and Ljungman M},

url = {www.nature.com/articles/srep43598},

doi = {10.1038/srep43598},

year  = {2017},

date = {2017-03-01},

journal = {Scientific reports},

volume = {7},

number = {1},

pages = {43598},

abstract = {In response to ionizing radiation (IR), cells activate a DNA damage response (DDR) pathway to re-program gene expression. Previous studies using total cellular RNA analyses have shown that the stress kinase ATM and the transcription factor p53 are integral components required for induction of IR-induced gene expression. These studies did not distinguish between changes in RNA synthesis and RNA turnover and did not address the role of enhancer elements in DDR-mediated transcriptional regulation. To determine the contribution of synthesis and degradation of RNA and monitor the activity of enhancer elements following exposure to IR, we used the recently developed Bru-seq, BruChase-seq and BruUV-seq techniques. Our results show that ATM and p53 regulate both RNA synthesis and stability as well as enhancer element activity following exposure to IR. Importantly, many genes in the p53-signaling pathway were coordinately up-regulated by both increased synthesis and RNA stability while down-regulated genes were suppressed either by reduced synthesis or stability. Our study is the first of its kind that independently assessed the effects of ionizing radiation on transcription and post-transcriptional regulation in normal human cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_280,

title = {DICER, DROSHA and DNA damage response RNAs are necessary for the secondary recruitment of DNA damage response factors.},

author = {Francia S and Cabrini M and Matti V and Oldani A and {d'Adda di Fagagna F}},

url = {http://jcs.biologists.org/content/129/7/1468.long},

doi = {10.1242/jcs.182188},

year  = {2016},

date = {2016-02-18},

journal = {Journal of Cell Science},

volume = {129},

pages = {1468-1476},

abstract = {The DNA damage response (DDR) plays a central role in preserving genome integrity. Recently, we reported that the endoribonucleases DICER and DROSHA contribute to DDR activation by generating small non-coding RNAs, termed DNA damage response RNA (DDRNA), carrying the sequence of the damaged locus. It is presently unclear whether DDRNAs act by promoting the primary recognition of DNA lesions or the secondary recruitment of DDR factors into cytologically detectable foci and consequent signal amplification. Here, we demonstrate that DICER and DROSHA are dispensable for primary recruitment of the DDR sensor NBS1 to DNA damage sites. Instead, the accumulation of the DDR mediators MDC1 and 53BP1 (also known as TP53BP1), markers of secondary recruitment, is reduced in DICER- or DROSHA-inactivated cells. In addition, NBS1 (also known as NBN) primary recruitment is resistant to RNA degradation, consistent with the notion that RNA is dispensable for primary recognition of DNA lesions. We propose that DICER, DROSHA and DDRNAs act in the response to DNA damage after primary recognition of DNA lesions and, together with γH2AX, are essential for enabling the secondary recruitment of DDR factors and fuel the amplification of DDR signaling. 2016. Published by The Company of Biologists Ltd.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}