MYC is, by almost any measure, the most consequential oncogene in human cancer biology. Deregulated in the vast majority of human tumours across virtually every tissue type, this protein has long been known as a master transcriptional amplifier — a molecular regulator that commandeers gene expression programmes to drive relentless proliferation, metabolic reprogramming, and tumour progression. Given this central role, it is perhaps unsurprising that MYC has been one of the most intensively pursued targets in oncology, and yet it has historically resisted pharmacological intervention to such an extent that it came to be labelled, perhaps prematurely, as ‘undruggable’. A study published in May 2026 in Genes & Development by Gabriel Cohn and colleagues at Oregon Health & Science University now offers a compelling reason to revisit that label — not because the transcriptional function of MYC has been rendered accessible to drugs, but because a second, entirely unexpected molecular role for MYC has been uncovered in the DNA damage response.
The scientific foundation of this work rests on a paradox that has puzzled researchers for years. On the one hand, the transcriptional activity of MYC creates substantial genomic burden: its capacity to amplify RNA polymerase II engagement across the genome generates torsional stress, R-loop formation, and transcription-replication conflicts that collectively inflict significant DNA damage on the cells in which MYC is overexpressed. On the other hand, tumours characterised by high MYC activity are notorious for their resistance to chemotherapy and other treatments that exploit DNA damage as a mechanism of cell killing. How the same protein could simultaneously generate and tolerate — or perhaps even repair — the genomic damage it helps create has remained poorly understood. Cohn and colleagues turned their attention to this question in the context of pancreatic ductal adenocarcinoma (PDAC), a malignancy chosen precisely because it combines unusually high MYC pathway activity with particularly poor responses to DNA-damaging therapies. Analysing transcriptomic data from 289 primary and metastatic PDAC tumours, the investigators found a striking co-occurrence between MYC pathway activation and gene expression signatures of both replication stress and DNA repair — a correlation consistent with a causal rather than a coincidental relationship between MYC activity and genomic repair capacity.
To investigate the underlying molecular mechanism, the team employed a technique known as the DNA double-strand break-specific proximity ligation assay, or DI-PLA, which allows researchers to visualise protein associations with sites of DNA breakage directly within intact cells. When PDAC cell lines were subjected to DNA damage — whether through bleomycin treatment or through the introduction of site-specific double-strand breaks using Cas9 targeting ribosomal DNA loci — MYC protein was reproducibly detected at or near the break sites. Importantly, this association intensified when cells were additionally exposed to replication stress induced by aphidicolin, an inhibitor of the replicative DNA polymerases. Under these stress conditions, MYC was also found to interact with two of the most important effectors of homologous recombination repair: BRCA1 and RAD51. These associations, detected by proximity ligation assay and confirmed to be stress-responsive rather than constitutive, suggest a model in which MYC dynamically relocates to sites of DNA damage and helps recruit the homologous recombination machinery.
The molecular determinant of this behaviour was identified as phosphorylation of MYC at serine 62, a post-translational modification designated pS62-MYC. This particular phosphoform was already known for its role in stabilising MYC and enhancing its transcriptional activity downstream of mitogenic signalling through RAS and cyclin-dependent kinases; what the current study reveals is that pS62-MYC is also indispensable for MYC’s recruitment to DNA damage sites. When the investigators introduced a phosphorylation-deficient S62A-MYC mutant that cannot be phosphorylated at this position, both the physical association of MYC with double-strand breaks and its interactions with BRCA1 and RAD51 were severely impaired. As a direct consequence, cells expressing S62A-MYC showed reduced capacity to repair DNA damage and a marked decrease in survival under genotoxic conditions. To characterise the broader proteome context of this function, the team employed proximity-dependent biotinylation using a MYC-BioID2 fusion construct, which confirmed that replication stress induces a global remodelling of the MYC interactome: associations with transcriptional regulatory proteins are progressively shed, while interactions with components of the DNA damage response pathway are selectively enriched. The result is a molecular portrait of MYC as a context-dependent dual-function protein — a transcriptional driver during normal growth conditions, and a genoprotective factor under genotoxic stress.
The therapeutic implications of this finding are substantial, and some are already being explored clinically. At OHSU, a window-of-opportunity trial is currently under way in which patients with advanced pancreatic cancer receive OMO-103, a first-in-class MYC inhibitor, followed by sequential tumour biopsies designed to map how pharmacological MYC blockade reshapes tumour biology in vivo. The present findings suggest that such inhibitors may operate through at least two mechanistically distinct pathways: impairing the transcriptional amplification of growth genes, and simultaneously disabling the genoprotective DNA repair function identified here. This convergence could in principle synergise powerfully with chemotherapy regimens based on DNA-damaging agents, or with PARP inhibitors in tumours harbouring BRCA1 or BRCA2 deficiencies. Unfortunately, several important limitations must be acknowledged before these perspectives can be translated into clinical strategies. The experimental platform of the study relies primarily on cell lines rather than primary tumours or in vivo models, and the precise structural basis of the pS62-MYC interaction with DNA break sites — whether it involves direct DNA binding, scaffolding by associated proteins, or spatial concentration within phase-separated nuclear compartments — has not yet been resolved. It also remains unclear whether this repair function is equally operative across all MYC-driven tumour types, or whether it is in some way specific to the high-replication-stress environment of PDAC. Taken together, however, these findings open a genuinely new chapter in MYC biology, establishing pS62-MYC as both a mechanistically novel regulator of genomic stability and a potentially actionable therapeutic vulnerability — one that sits at the intersection of oncogenesis and DNA damage signalling, where some of the most consequential opportunities in cancer pharmacology may yet be found.
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