POGZ promotes homology-directed DNA repair in an HP1-dependent manner

The heterochromatin protein HP1 plays a central role in genome stability, but how HP1 is regulated during DNA repair is not well understood. Here we show that the zinc-finger protein POGZ promotes the presence of HP1 at DNA double-strand breaks (DSBs) in human cells. POGZ depletion delays DSB resolution and sensitizes cells to DNA-damaging agents like cisplatin and PARP inhibitors. Mechanistically, POGZ facilitates homology-directed DNA repair by recruiting/retaining the BRCA1–BARD1 repair complex at DSB sites in an HP1-dependent manner. In vivo, Pogz haploinsufficiency in mice (Pogz^+/Δ^) causes developmental delay, impaired learning, hyperactivity, immune defects, and radiosensitivity with accumulation of DNA damage – mirroring key features of White–Sutton syndrome. Conclusions: POGZ is identified as a critical factor in the homologous recombination repair pathway, linking heterochromatin dynamics (HP1) with the BRCA1/BARD1-mediated DSB repair. These findings establish a role for POGZ in DNA repair and explain how POGZ loss-of-function can lead to developmental syndromes by compromising genomic stability.