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

• DOI: 10.1101/2023.04.21.537819
• Publication Date: 2023-04-22T00:00:25Z
• Authors: Romuald Binet; Jean-Philippe Lam...; Marketa Tomkova; Samuel Tischfield; Arianna Baggiolini; Sarah Picaud; Sovan Sarkar; Pakavarin Louphra...; Diogo Dias; Suzanne Carreira; Timothy Humphrey; Panagis Fillipako...; Richard White; Colin R Goding
• Keywords: Microphthalmia-associated transcription factor; Rad50

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