Program Faculty

My laboratory studies a single mechanistic question: how do defects in the fundamental machinery of DNA replication, repair, and transcription generate the genomic instability that initiates cancer? When replication, transcription, and repair fall out of balance, structurally difficult regions of the genome, (repetitive elements, common fragile sites) become hypermutable. We study the basis of that hypermutability with a deliberate emphasis on the earliest, pre-malignant stages of disease, on the reasoning that a mechanism generating hypermutability in a pre-malignant clone is also a vulnerability that can be targeted before transformation occurs. Prevention, not only treatment, is the endpoint we are building toward. The technical engine of this work is locus-specific Single Molecule Analysis of Replicated DNA (SMARD), which resolves replication fork dynamics at individual loci on single DNA fibers, combined with cytogenetics, genome-wide replication profiling, and computational genomics.. We have pursued this question in four settings. In Fanconi anemia, we defined how FANCD2 and translesion polymerase eta enable replication through common fragile sites, and are now resolving the sequence motifs that make particular loci break. In Adult T-cell leukemia/lymphoma, we showed that EP300 loss causes chronic replication stress and reduced BRCA2 expression, making EP300-mutant cells phenocopy BRCA-deficient cancers, converting a prognostic mutation into an actionable therapeutic vulnerability, and forming the basis of my NCI R01. In World Trade Center–exposed first responders, we supplied the mechanistic link between particulate exposure and somatic mutagenesis underlying their elevated clonal hematopoiesis burden, and subsequently identified IL1RAP as a candidate target for intercepting clonal expansion. Most recently, we produced the first experimental evidence that the synthetic azo dyes Red 40 and Yellow 6 damage DNA in human cells, with that damage markedly amplified in Fanconi anemia and BRCA2-deficient backgrounds. Our objectives for the coming years follow directly from these lines. We will test whether the BRCA-like vulnerability in EP300-mutant ATLL can be exploited therapeutically in vivo and in patient-derived models, with the aim of an investigator-initiated trial in a disease that urgently needs one. We will determine whether azo dye exposure measurably elevates cancer risk in DNA repair–deficient individuals, a question with implications for clinical counseling and regulatory policy. We will complete the sequence-resolved model of fragile-site instability and extend it genome-wide. The through-line is to take one deep mechanistic question: how replication stress generates mutation, and follow it wherever it is most consequential: into an inherited cancer predisposition syndrome, an aggressive leukemia, a first-responder population, and the food supply.

Publications