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  1. Article ; Online: DNA damage remodels the MITF interactome to increase melanoma genomic instability.

    Binet, Romuald / Lambert, Jean-Philippe / Tomkova, Marketa / Tischfield, Samuel / Baggiolini, Arianna / Picaud, Sarah / Sarkar, Sovan / Louphrasitthiphol, Pakavarin / Dias, Diogo / Carreira, Suzanne / Humphrey, Timothy C / Fillipakopoulos, Panagis / White, Richard / Goding, Colin R

    Genes & development

    2024  Volume 38, Issue 1-2, Page(s) 70–94

    Abstract: Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA damage response (DDR) programs. However, some cells (for example, in skin) are normally exposed to high levels of DNA-damaging ... ...

    Abstract Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA damage response (DDR) programs. However, some cells (for example, in skin) are normally exposed to high levels of DNA-damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Using melanoma as a model, we show here that the microphthalmia-associated transcription factor MITF, a lineage addition oncogene that coordinates many aspects of melanocyte and melanoma biology, plays a nontranscriptional role in shaping the DDR. On exposure to DNA-damaging agents, MITF is phosphorylated at S325, and its interactome is dramatically remodeled; most transcription cofactors dissociate, and instead MITF interacts with the MRE11-RAD50-NBS1 (MRN) complex. Consequently, cells with high MITF levels accumulate stalled replication forks and display defects in homologous recombination-mediated repair associated with impaired MRN recruitment to DNA damage. In agreement with this, high MITF levels are associated with increased single-nucleotide and copy number variant burdens in melanoma. Significantly, the SUMOylation-defective MITF-E318K melanoma predisposition mutation recapitulates the effects of DNA-PKcs-phosphorylated MITF. Our data suggest that a nontranscriptional function of a lineage-restricted transcription factor contributes to a tissue-specialized modulation of the DDR that can impact cancer initiation.
    MeSH term(s) Humans ; Melanoma/genetics ; Microphthalmia-Associated Transcription Factor/genetics ; DNA Damage ; Genomic Instability/genetics ; DNA
    Chemical Substances Microphthalmia-Associated Transcription Factor ; DNA (9007-49-2) ; MITF protein, human
    Language English
    Publishing date 2024-02-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.350740.123
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: DNA damage-induced interaction between a lineage addiction oncogenic transcription factor and the MRN complex shapes a tissue-specific DNA Damage Response and cancer predisposition.

    Binet, Romuald / Lambert, Jean-Philippe / Tomkova, Marketa / Tischfield, Samuel / Baggiolini, Arianna / Picaud, Sarah / Sarkar, Sovan / Louphrasitthiphol, Pakavarin / Dias, Diogo / Carreira, Suzanne / Humphrey, Timothy / Fillipakopoulos, Panagis / White, Richard / Goding, Colin R

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA Damage Response (DDR) programs. However, some cells, in skin for example, are normally exposed to high levels of DNA damaging ... ...

    Abstract Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA Damage Response (DDR) programs. However, some cells, in skin for example, are normally exposed to high levels of DNA damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Here we show, using melanoma as a model, that the microphthalmia-associated transcription factor MITF, a lineage addition oncogene that coordinates many aspects of melanocyte and melanoma biology, plays a non-transcriptional role in shaping the DDR. On exposure to DNA damaging agents, MITF is phosphorylated by ATM/DNA-PKcs, and unexpectedly its interactome is dramatically remodelled; most transcription (co)factors dissociate, and instead MITF interacts with the MRE11-RAD50-NBS1 (MRN) complex. Consequently, cells with high MITF levels accumulate stalled replication forks, and display defects in homologous recombination-mediated repair associated with impaired MRN recruitment to DNA damage. In agreement, high MITF levels are associated with increased SNV burden in melanoma. Significantly, the SUMOylation-defective MITF-E318K melanoma predisposition mutation recapitulates the effects of ATM/DNA-PKcs-phosphorylated MITF. Our data suggest that a non-transcriptional function of a lineage-restricted transcription factor contributes to a tissue-specialised modulation of the DDR that can impact cancer initiation.
    Language English
    Publishing date 2023-04-21
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.21.537819
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response.

    Ghari, Fatemeh / Quirke, Anne-Marie / Munro, Shonagh / Kawalkowska, Joanna / Picaud, Sarah / McGouran, Joanna / Subramanian, Venkataraman / Muth, Aaron / Williams, Richard / Kessler, Benedikt / Thompson, Paul R / Fillipakopoulos, Panagis / Knapp, Stefan / Venables, Patrick J / La Thangue, Nicholas B

    Science advances

    2016  Volume 2, Issue 2, Page(s) e1501257

    Abstract: Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains ... ...

    Abstract Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to an acetylated domain in E2F-1, and PAD4 and BRD4 coexist with E2F-1 on cytokine gene promoters. Accordingly, the combined inhibition of PAD4 and BRD4 disrupts the chromatin-bound complex and suppresses cytokine gene expression. In the murine collagen-induced arthritis model, chromatin-bound E2F-1 in inflammatory cells and consequent cytokine expression are diminished upon small-molecule inhibition of PAD4 and BRD4, and the combined treatment is clinically efficacious in preventing disease progression. Our results shed light on a new transcription-based mechanism that mediates the inflammatory effect of PAD4 and establish the interplay between citrullination and acetylation in the control of E2F-1 as a regulatory interface for driving inflammatory gene expression.
    MeSH term(s) Acetylation ; Animals ; Arthritis, Experimental/genetics ; Arthritis, Experimental/immunology ; Arthritis, Experimental/metabolism ; Cell Cycle Proteins ; Cell Line ; Citrulline/metabolism ; Cytokines/genetics ; E2F1 Transcription Factor/chemistry ; E2F1 Transcription Factor/genetics ; E2F1 Transcription Factor/metabolism ; Gene Expression Regulation ; HL-60 Cells ; Humans ; Hydrolases/antagonists & inhibitors ; Hydrolases/genetics ; Hydrolases/metabolism ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/metabolism ; Male ; Mice ; Mice, Inbred DBA ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic ; Protein-Arginine Deiminase Type 4 ; Protein-Arginine Deiminases ; RNA, Small Interfering/genetics ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Transcription Factors/metabolism
    Chemical Substances BRD4 protein, human ; Cell Cycle Proteins ; Cytokines ; E2F1 Transcription Factor ; E2F1 protein, human ; Nuclear Proteins ; RNA, Small Interfering ; Recombinant Proteins ; Transcription Factors ; Citrulline (29VT07BGDA) ; Hydrolases (EC 3.-) ; PADI4 protein, human (EC 3.5.3.15) ; Protein-Arginine Deiminase Type 4 (EC 3.5.3.15) ; Protein-Arginine Deiminases (EC 3.5.3.15) ; peptidylarginine deiminase 4, mouse (EC 3.5.3.15)
    Language English
    Publishing date 2016-02-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.1501257
    Database MEDical Literature Analysis and Retrieval System OnLINE

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