Abstract 5408: Unraveling c-MYC role in DNA replication origin licensing through non-canonical pathways

Abstract Origin licensing is essential for DNA replication, confined to the G1 phase of the cell cycle, where human cells must license thousands of origins to ensure complete genome duplication. Insufficient licensing, or "underlicensing", leads to genome instability and increased sensitivity to chemotherapeutic agents. Altered G1 duration and dysregulated origin licensing are characteristic features of many cancers, potentially contributing to their aberrant cell proliferation. However, how origin licensing rates are controlled in cells with varying G1 lengths is poorly understood. Our research reveals that while cyclin E1 overproduction shortens G1 and causes severe underlicensing, c-MYC overproduction also shortens G1 but uniquely accelerates licensing, preventing underlicensing. *We identified a separation of function c-MYC mutant that fails to induce rapid licensing despite upregulating mRNA levels of licensing factors akin to wild-type c-MYC, indicating the involvement of non-canonical pathways beyond traditional transcriptional mechanisms*. c-MYC influence on global chromatin structure through hyperacetylation is pivotal. Our data show that c-MYC’s role in licensing acceleration depends on the recruitment of TRRAP—a transcription cofactor involved in chromatin modification—and the histone acetyltransferase GCN5. Notably, euchromatin is preferred for origin licensing in early G1. We hypothesize that heterochromatin may be rapidly licensed in c-MYC overproducing cells to compensate for potential underlicensing. We are currently profiling early versus late G1 cells overproducing c-MYC to determine the genomic locations of the licensed origins. Unraveling c-MYC downstream pathways regulating origin licensing could revolutionize therapeutic strategies by precisely controlling proliferation in MYC-driven cancers, increasing their sensitivity to DNA-damaging treatments, and paving the way for targeting non-canonical pathways in cancer therapy. Citation Format: Dalia Fleifel, Eiman Elkoumy, Arthi Adavikolanu, Sidra Qayyum, Jeanette Cook. Unraveling c-MYC role in DNA replication origin licensing through non-canonical pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5408.