Structural basis of thymidine-rich DNA recognition by Drosophila P75 PWWP domain

dP75, a homolog of the human HIV host factor LEDGF, plays a crucial role in protecting oogenesis by recruiting the histone kinase Jil-1 to euchromatin and consequently impeding the spreading of H3K9me2. Like LEDGF, dP75 binds to transcriptionally active chromatin regions. However, the precise molecular mechanism underlying dP75's binding to chromatin remains unknown. We determined the crystal structures of the dP75 PWWP domain in its apo form and in complex with ssDNA. dP75 PWWP forms a domain-swapped homodimer both in vitro and in vivo. Mutation in key residues, especially within the aromatic cage, resulted in phenotypes similar to dP75 knockout mutants, such as impaired chromatin binding, transposon upregulation, and female sterility.