Abstract: Genome Stability (GS) The Genome Stability (GS) Program is devoted to understanding the molecular pathways that maintain genome integrity, how these processes are altered in cancer cells, and finally how these alterations may be exploited to kill tumor cells. This program has four broad themes: (1) mechanisms of genome stability, (2) radiation and oxidative damage, (3) genotoxic stress responses, and (4) aging and cancer. Fundamental research in genome stability is essential for advancing understanding of the mechanisms of tumor formation and provides a valuable source of novel targets and strategies for cancer diagnosis, treatment, and prevention. Significant highlights of the program have been seminal discoveries regarding the action of DNA repair proteins at the single molecule level, the use of targeted oxidative base damage at telomeres to study subsequent telomere dysfunction, the role of the alternative lengthening of telomere (ALT) pathway in aggressive neuroblastoma tumors, development of approaches to mitigate radiation damage, mechanistic insights into cell death pathways including ferroptosis, and the use of ATR inhibitors in conjunction with ionizing radiation or cisplatin to kill tumor cells through enhanced immune responses. Growth and impact of the program has been greatly enhanced by recruiting 18 new faculty from across the University of Pittsburgh and through HCC-supported recruitment. This Program is co-directed by Patricia Opresko, PhD and Bennett Van Houten, PhD. Dr. Opresko is a Professor of Environmental and Occupational Health who is internationally recognized for her work on molecular insights into telomere biology and provides important links to Genome Stability Program (GS) and catchment area scientists. Dr. Van Houten is the Richard M. Cyert Professor of Molecular Oncology in the Department of Pharmacology and Chemical Biology and is a world expert on molecular mechanisms of DNA repair and mitochondrial biology. Their research interests are complementary and provide strong synergy. Since 2015, the number of faculty working in the area of genome stability and cancer has increased from 20 to 38 members, from 14 departments and 3 schools within the University of Pittsburgh and a core group of 13 independent faculty laboratories housed within the HCC Building. GS members conduct cancer-focused research supported by $6.5M in total annual direct funding of which $2.8M is NCI funding, $3.4M is other peer-reviewed and $0.3M is non-peer-reviewed. From 2015-August 2019, GS members published 516 cancer-related publications representing 20% intra-programmatic, 40% inter- programmatic, and 69% inter-institutional collaborations.