Abdulaziz B. Hamid, Lauren E. Frank, Devi D. Nelakurti, Anna Valentine, Mehak Kaur, Ali Latif, Renee A. Bouley, Ruben C. Petreaca

Abstract B007: Mutations in chromatin remodelers produce intra-chromosomal deletions in cancer cells

  • Cancer Research
  • Oncology
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Abstract Cancer cells are characterized by chromosomal re-arrangements which range from small deletions and insertions (InDels) to complete genome re-organization such as kataegis and chromothripsis. These genomic re-arrangements accompanied by other mutation signatures act as drivers of cellular transformation and immortalization. One form of re-arrangement is the intra-chromosomal deletion (ICD) which is larger than an InDel and can wipe out entire genomic sequences. Recurrent ICDs have been shown to inactivate key cell cycle regulators (e.g., Rb, PTEN, TP53) and contribute to cellular transformation. However, cancer cells are replete with ICDs of unknown function. ICDs arise due to failure of the DNA double strand break (DSB) repair machinery but the mechanism remains elusive. Mutations in three Mutations in key DNA damage repair genes such as the breast cancer susceptibility genes BRCA1 and BRCA2 as well as the accessory gene RAD52 accelerate ICD formation. Using the yeast model system, we identified physical and genetic interactions between RAD52 and two chromatin remodeling factors (KAT5 and HIRA). KAT5 is a histone acetyltransferase with functions in both transcription and DSB repair while HIRA is a histone chaperone required for re-deposition of nucleosomes following repair. We will present results from computational analysis of cancer genomes as well as experimental bench data that show that mutations in KAT5 and HIRA affect ICD formation. Epistatic analysis between the histone remodelers and BRCA1, BRCA2 and RAD52 reveals that co-occurring mutations contribute to destabilization of the repair machinery. In silico protein structure analysis was performed to model how mutations affect the function of these enzymes. Our data uncovers unexpected functions of chromatin remodelers in modulating the function of DNA recombinases and other accessory factors. Citation Format: Abdulaziz B. Hamid, Lauren E. Frank, Devi D. Nelakurti, Anna Valentine, Mehak Kaur, Ali Latif, Renee A. Bouley, Ruben C. Petreaca. Mutations in chromatin remodelers produce intra-chromosomal deletions in cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B007.

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