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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.
Afiliação
  • Binet R; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  • Lambert JP; Department of Molecular Medicine, Cancer Research Center, Université Laval, Québec City, Québec G1V 4G2, Canada.
  • Tomkova M; Endocrinology-Nephrology Axis, CHU de Québec-Université Laval Research Center, Québec City, Québec G1V 4G2, Canada.
  • Tischfield S; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  • Baggiolini A; Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, California 95616, USA.
  • Picaud S; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • Sarkar S; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • Louphrasitthiphol P; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • Dias D; Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • Carreira S; Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
  • Humphrey TC; Cancer Research UK, Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom.
  • Fillipakopoulos P; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  • White R; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  • Goding CR; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
Genes Dev ; 38(1-2): 70-94, 2024 02 13.
Article em En | MEDLINE | ID: mdl-38316520
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Melanoma Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Melanoma Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article