BRCA1-A and LIG4 complexes mediate ecDNA biogenesis and cancer drug resistance.

ABSTRACT: Extrachromosomal circular DNA (ecDNA) are commonly produced within the nucleus to drive genome dynamics and heterogeneity, enabling cancer cell evolution and adaptation. However, the mechanisms underlying ecDNA biogenesis remain poorly understood. Here using genome-wide CRISPR screening in human cells, we identified the BRCA1-A and the LIG4 complexes mediate ecDNA production. Following DNA fragmentation, the upstream BRCA1-A complex protects DNA ends from excessive resection, promoting end-joining for circularization. Conversely, the MRN complex, which mediates end resection and thus antagonizes the BRCA1-A complex, suppresses ecDNA formation. Downstream, LIG4 conservatively catalyzes ecDNA production in Drosophila and mammals, with patient tumor ecDNA harboring junctions marked by

SUBMITTER: Chung OW 

PROVIDER: S-EPMC11870461 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature