A new study reveals that the CHAMP1 complex — which includes POGZ, HP1α, and the enzyme SETDB1 — helps protect cells from replication stress, a type of DNA damage that can drive cancer. When DNA replication stalls, the complex is recruited to the site and adds repressive chemical marks to the surrounding DNA, stabilizing the stalled fork and preventing it from being degraded. Cells lacking CHAMP1 become more unstable and more sensitive to replication stress, and the study found that disabling CHAMP1 alongside another pathway can selectively kill certain cancer cells. These findings suggest that POGZ and its partners may be potential targets for treating cancers that already carry high levels of replication stress.