Adam Krysztofiak

Yale University | YU · Department of Therapeutic Radiology

DNA- and histone-related research frequently comprises the quantitative analysis of protein modifications, such as histone phosphorylation. Analysis of accumulation and disappearance of protein foci are used to monitor DNA damage and repair kinetics. If the protein of interest doesn’t accumulate in foci, laser micro-irradiation of single nuclei pro...

Technical improvements in clinical radiotherapy for maximizing cytotoxicity to the tumor while limiting negative impact on co-irradiated healthy tissues include the increasing use of particle therapy (e.g., proton therapy) worldwide. Yet potential differences in the biology of DNA damage induction and repair between irradiation with X-ray photons a...

Exploitation of DNA repair defects has enabled major advances in treating specific cancers. Recent work discovered that the oncometabolite 2-hydroxyglutarate (2-HG), produced by neomorphic isocitrate dehydrogenase 1/2 (IDH1/2) mutations, confers a homology-directed repair (HDR) defect through 2-HG–induced histone hypermethylation masking HDR signal...

Gene amplification drives oncogenesis in a broad spectrum of cancers. A number of drugs have been developed to inhibit the protein products of amplified driver genes, but their clinical efficacy is often hampered by drug resistance. Here, we introduce a therapeutic strategy for targeting cancer-associated gene amplifications by activating the DNA d...

Cancer bioenergetics fuel processes necessary to maintain viability and growth under stress conditions. We hypothesized that cancer metabolism supports the repair of radiation-induced DNA double-strand breaks (DSBs). We combined the systematic collection of metabolic and radiobiological data from a panel of irradiated cancer cell lines with mathema...

Monoclonal antibody therapies for cancer have demonstrated extraordinary clinical success in recent years. However, these strategies are thus far mostly limited to specific cell surface antigens, even though many disease targets are found intracellularly. Here we report studies on the humanization of a full-length, nucleic acid binding, monoclonal...

The BRCA2 germline missense variant, R3052W, resides in the DNA binding domain and has been previously classified as a pathogenic allele. In this study, we sought to determine how R3052W alters the cellular functions of BRCA2 in the DNA damage response. The BRCA2 R3052W mutated protein exacerbates genome instability, is unable to rescue homology-di...

p>Flexibility and reprogramming of cancer metabolism supports cancer progression and therapy resistance. In previous work we described opportunities for overcoming environment-induced resistance to ionizing radiation (IR) by pharmacologic inhibition of metabolic processes [1,2,3]. Here, we hypothesized that certain aspects of cancer metabolism will...

ICRR 2019 - Poster #429 - 1. Basic Mechanisms

Proton beam therapy is increasingly applied for the treatment of human cancer, as it promises to reduce normal tissue damage. However, little is known about the relationship between linear energy transfer (LET), the type of DNA damage, and cellular repair mechanisms, particularly for cells irradiated with protons. We irradiated cultured cells deliv...

The survival kinase protein kinase B (Akt) participates in the regulation of essential subcellular processes, e.g., proliferation, growth, survival, and apoptosis, and has a documented role in promoting resistance against genotoxic stress including radiotherapy, presumably by influencing the DNA damage response and DNA double-strand break (DSB) rep...

The quantitative analysis of cells and foci plays a key role in various cell biological methods. In the field of radiation biology and molecular radiation oncology, the effect of ionizing radiation, chemotherapy or molecularly targeted drugs on DNA damage induction is detected by the analysis of protein clusters or phosphorylated proteins recruited...

The quantitative analysis of foci plays an important role in various cell biological methods. In the fields of radiation biology and experimental oncology, the effect of ionizing radiation, chemotherapy or molecularly targeted drugs on DNA damage induction and repair is frequently performed by the analysis of protein clusters or phosphorylated prot...

The quantitative analysis of cells and foci plays an important role in various cell biology methods. In the fields of radiation biology and molecular radiation oncology, the effect of ionizing radiation, chemotherapy or molecularly targeted drugs on DNA damage induction is performed by the analysis of protein clusters or phosphorylated proteins rec...

Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of th...

The transcription factor Nrf2 controls the expression of genes encoding cytoprotective enzymes and proteins. Its activation is related to conformational changes in the inhibitory protein Keap1 and/or Nrf2 phosphorylation by upstream kinases. Activation of Nrf2 can lead to the induction of phase II enzymes responsible for the inactivation of potenti...

UDP-glucuronosyltransferases (UGTs) are important detoxifi cation and drug-metabolizing enzymes, which catalyse the glucuronidation of exogenous and endogenous chemicals. The anti-carcinogenic activity of dietary phytochemicals is partly attributed to the induction of phase II enzymes, including UGT1A. Our earlier study showed that protocatechuic a...