A study led by Ludwig Oxford’s Colin Goding and alumnus Romuald Binet showed that the microphthalmia-associated transcription factor MITF shapes melanocyte responses to DNA damage in an unexpected way. The researchers reported in a February paper in Genes & Development that DNA-damaging agents induce MITF phosphorylation on serine 325 and alter the protein’s interaction with other proteins. MITF then dissociates from its usual partners involved in gene expression and now interacts with the MRN protein complex, which repairs DNA and triggers cell cycle arrest. This stalls the DNA repair pathway, contributing to genomic instability. In agreement with this, high MITF levels are associated with increased single-nucleotide mutations and copy number abnormalities in the genomes of cancerous melanocytes. Notably, a mutation in MITF (E381K) that is known to predispose people to melanoma recapitulates the observed effects of MITF phosphorylation—suggesting a mechanism for the cancer risk associated with the mutation. The authors speculate that under physiological conditions, the penalty imposed by potential genome instability caused by reduced MRN complex function when it is bound by MITF would be offset by increased melanocyte proliferation and their ultimate differentiation that would protect against subsequent DNA damage.
DNA damage remodels the MITF interactome to increase melanoma genomic instability
Genes & Development, 2024 February 5