The way in which DNA is organized in the cell influences how the genetic code of the DNA is processed in a process called transcription. In this project, I have visualized the interplay between DNA organization and the reading of the genetic code using microscopy. I have shown that gaining accessibility to the DNA is important for the start of each burst of transcription.

In this project a series of cryo-EM structures result in a movie of different conformations in DNA mismatch repair proteins. These novel structures ezplain molecular mechanisms in this critical DNA repair system. They also helped to explain the origin of a particular mildly pathogenic mutation that leads to constitutive DNA mismatch deficiency (CMMRD).

A diet for a stronger immunotherapy Immunotherapy is mostly only effective in tumors with a high load of genetic mutations. We showed that amino acid deprivation of cancer cells generates proteins with altered sequences. However, these proteins remain intra-cellular and are blocked from further processing into peptides for presentation to the immune system. This proposal aims to identify genetic and chemical tools that can release this block and allow presentation of altered peptides in cancer cells treated with amino acid deprivation. Successful research will open up possibilities of using diet to improve immunotherapy treatment of cancers with low mutational burden.

The genetic information in our genome is organized into varying architectures of epigenetic states in different cell types. The exact function of these domains in the regulation of gene expression is poorly understood. Our proposal aims at better understanding the influence of local chromatin environment on gene expression specially promoter activity. Using high-throughput methods including a novel technology we will investigate alterations in transcription activity of a group of promoters when integrated at thousands of different locations in the genome serving as sensors of local chromatin influence on transcription. This will generate a detailed description of how different genetic (DNA regulatory elements) and epigenetic configurations interact with each other in the nucleus. Next, we aim to study the functional effects of epigenetic inhibitors on this interaction. Additionally, we will study how dynamics of transcription activation are regulated by local chromatin context and how transcription activation at one locus affects the adjacent genes. Altogether, our proposal has the potential to unravel the functional significance of different chromatin states and to provide the mechanistic details of how epigenetic drugs of medical significance influence chromatin in a functional manner.

Young adult cancer patients (18-39 years) form a unique group. While they try to achieve developmental milestones, they are confronted with a life-threatening, for their age rare disease, and its aggressive treatment. This study will examine which young adult cancer patients are at risk for poor health outcomes and why.