Functional study of GEN1 in safeguarding genome stability and maintenance of embryonic stem cells

Abstract

Embryonic stem cells rely on robust DNA repair to preserve genome stability despite their rapid proliferation. This thesis identifies the Holliday Junction resolvase GEN1 as a crucial safeguard in these cells, as its loss compromises viability and leads to persistent DNA damage signalling, chromosomal fusions and defective processing of replication associated intermediates upon replication stress. Notably, both catalytically active and inactive GEN1 restore colony formation, pointing to potential nuclease independent roles. Overall, the work reveals GEN1 as a key guardian of genome integrity in embryonic stem cells.