EXD2 is a 3'-5' exonuclease with dual catalytic activities depending on cofactor availability 12. In the presence of Mg2+, it exhibits 3'-5' exoribonuclease activity, while Mn2+ enables both exoribonuclease and exodeoxyribonuclease activities 12. EXD2 functions in multiple DNA homeostasis pathways. Nuclearly, it promotes homologous recombination by facilitating double-strand break resection through interaction with the MRN complex 3. EXD2 also protects stalled replication forks by restraining excessive fork regression, preventing fork collapse and enabling restart 4. Recently, EXD2 was identified as a pivotal R-loop resolvase that, upon PARP1-mediated recruitment via poly(ADP-ribose) binding, preferentially degrades RNA strands within R-loops to resolve these structures and maintain genome stability 5. Additionally, EXD2 directs telomere maintenance through alternative lengthening pathways in cancer cells by orchestrating replication fork processing 6. Clinically, EXD2 depletion shows synthetic lethality with BRCA1/2 mutations 4, suggesting therapeutic potential. Structurally, EXD2 contains an N-terminal mitochondrial outer membrane anchor with a cytosolic C-terminal exonuclease domain 2, enabling both mitochondrial and nuclear functions.