DNA Damage Repair (DDR) mechanisms are often conserved across different tissue types, but increasing evidence suggests that their function might be modulated by tissue-restricted factors that would tailor repair pathways to reflect the demands of the specific cell types. The Goding lab, with support from Ludwig Oxford's Richard White and Marketa Tomkova, look to understand the role of MITF in coordinating these response mechanisms in melanoma.
Romuald Binet and colleagues within the Goding lab show that MITF expression is correlated with replication stress and genomic instability and that the MITF interactome is dramatically remodelled following DNA damage. They demonstrate that MITF is phosphorylated at S325 upon exposure to DNA damaging agents, causing most of the transcription co-factors to dissociate, leading MITF to instead interact with the MRN complex. This led cells with high levels of MITF to accumulate stalled replication forks and increased single nucleotide and copy number variant burden in melanoma. The group propose that the transcription factor-dependent regulation of the DDR might be a general mechanism that allows fine tuning of the repair processes, depending on the tissue or the context.
To find out more about how MITF can shape the response to DNA damage, and to read about mechanistic reasoning for how the E318K mutation impacts predisposition to melanoma, read the full article here.