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Fabrizio D'adda Di Fagagna - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacological boost of DNA Damage Response and repair by enhanced biogenesis of DNA Damage Response RNAs.
    Scientific reports, 2019
    Co-Authors: Ubaldo Gioia, Sofia Francia, Matteo Cabrini, Silvia Brambillasca, Flavia Michelini, Corey Winston Jones-weinert, Fabrizio D'adda Di Fagagna
    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.

  • DICER, DROSHA and DNA Damage Response RNAs are necessary for the secondary recruitment of DNA Damage Response factors.
    Journal of cell science, 2016
    Co-Authors: Sofia Francia, Matteo Cabrini, Valentina Matti, Amanda Oldani, Fabrizio D'adda Di Fagagna
    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.

  • living on a break cellular senescence as a DNA Damage Response
    Nature Reviews Cancer, 2008
    Co-Authors: Fabrizio D'adda Di Fagagna
    Abstract:

    Cellular senescence is associated with ageing and cancer in vivo and has a proven tumour suppressive function. This Review discusses the evidence indicating that DNA Damage and the engagement of the DNA-Damage Response pathways are common to both ageing and cancer.

Joris Pothof - One of the best experts on this subject based on the ideXlab platform.

  • The DNA Damage Response: the omics era and its impact.
    DNA repair, 2014
    Co-Authors: Kasper W.j. Derks, Jan H J Hoeijmakers, Joris Pothof
    Abstract:

    The emergence of high density technologies monitoring the genome, transcriptome and proteome in relation to genotoxic stress have tremendously enhanced our knowledge on global Responses and dynamics in the DNA Damage Response, including its relation with cancer and aging. Moreover, ‘-omics’ technologies identified many novel factors, their post-translational modifications, pathways and global Responses in the cellular Response to DNA Damage. Based on omics, it is currently estimated that thousands of gene(product)s participate in the DNA Damage Response, recognizing complex networks that determine cell fate after Damage to the most precious cellular molecule, DNA. The development of next generation sequencing technology and associated specialized protocols can quantitatively monitor RNA and DNA at unprecedented single nucleotide resolution. In this review we will discuss the contribution of omics technologies and in particular next generation sequencing to our understanding of the DNA Damage Response and the future prospective of next generation sequencing, its single cell application and omics dataset integration in unraveling intricate DNA Damage signaling networks.

  • MicroRNAs, the DNA Damage Response and cancer.
    Mutation research, 2011
    Co-Authors: Maikel D Wouters, Dik C Van Gent, Jan H J Hoeijmakers, Joris Pothof
    Abstract:

    Many carcinogenic agents such as ultra-violet light from the sun and various natural and man-made chemicals act by damaging the DNA. To deal with these potentially detrimental effects of DNA Damage, cells induce a complex DNA Damage Response (DDR) that includes DNA repair, cell cycle checkpoints, Damage tolerance systems and apoptosis. This DDR is a potent barrier against carcinogenesis and defects within this Response are observed in many, if not all, human tumors. DDR defects fuel the evolution of precancerous cells to malignant tumors, but can also induce sensitivity to DNA damaging agents in cancer cells, which can be therapeutically exploited by the use of DNA damaging treatment modalities. Regulation of and coordination between sub-pathways within the DDR is important for maintaining genome stability. Although regulation of the DDR has been extensively studied at the transcriptional and post-translational level, less is known about post-transcriptional gene regulation by microRNAs, the topic of this review. More specifically, we highlight current knowledge about DNA Damage responsive microRNAs and microRNAs that regulate DNA Damage Response genes. We end by discussing the role of DNA Damage Response microRNAs in cancer etiology and sensitivity to ionizing radiation and other DNA damaging therapeutic agents.

Evi Soutoglou - One of the best experts on this subject based on the ideXlab platform.

L. Bryan Ray - One of the best experts on this subject based on the ideXlab platform.

  • Mammalian DNA Damage Response
    Science Signaling, 2011
    Co-Authors: L. Bryan Ray
    Abstract:

    To identify previously unrecognized components of a mammalian DNA Damage Response system, Cotta-Ramusino et al . used a large-scale screen of small interfering RNAs in a human tumor cell line. A group of about 100 genes were identified that were necessary to keep cells with Damaged DNA from proceeding into mitosis. Two of the proteins that localized at sites of DNA Damage were CLOCK and RHINO. CLOCK is a transcription factor that functions as part of the circadian clock, and RHINO is a component of a complex of proteins that act together to stimulate activity of the protein kinase ATR, which propagates the signal to arrest the cell cycle and allow DNA repair. C. Cotta-Ramusino, E. R. McDonald III, K. Hurov, M. E. Sowa, J. W. Harper, S. J. Elledge, A DNA Damage Response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling. Science 332 , 1313–1317 (2011). [Abstract][Full Text]

Fabrizio D'adda Di Fagagna - One of the best experts on this subject based on the ideXlab platform.

  • Living on a break: Cellular senescence as a DNA-Damage Response
    Nature Reviews Cancer, 2008
    Co-Authors: Fabrizio D'adda Di Fagagna
    Abstract:

    Cellular senescence is associated with ageing and cancer in vivo and has a proven tumour-suppressive function. Common to both ageing and cancer is the generation of DNA Damage and the engagement of the DNA-Damage Response pathways. In this Review, the diverse mechanisms that lead to DNA-Damage generation and the activation of DNA-Damage-Response signalling pathways are discussed, together with the evidence for their contribution to the establishment and maintenance of cellular senescence in the context of organismal ageing and cancer development.