PHF6 promotes non‐homologous end joining and G2 checkpoint recovery

The cellular response to DNA breaks is influenced by chromatin compaction. To identify chromatin regulators involved in the DNA damage response, we screened for genes that affect recovery following DNA damage using an RNAi library of chromatin regulators. We identified genes involved in chromatin remodeling, sister chromatid cohesion, and histone acetylation not previously associated with checkpoint recovery. Among these is the PHD finger protein 6 (PHF6), a gene mutated in Börjeson–Forssman–Lehmann syndrome and leukemic cancers. We find that loss of PHF6 dramatically compromises checkpoint recovery in G2 phase cells. Moreover, PHF6 is rapidly recruited to sites of DNA lesions in a PARP‐dependent manner and required for efficient DNA repair through classical non‐homologous end joining. These results indicate that PHF6 is a novel DNA damage response regulator that promotes end joining‐mediated repair, thereby stimulating timely recovery from the G2 checkpoint. Synopsis The PHD finger protein PHF6 is required for recovery from the DNA damage checkpoint and for viability after DSBs by promoting classical non‐homologous end joining. A genetic screen identifies novel chromatin regulators involved in DNA damage checkpoint recovery. Loss of PHF6 leads to DNA damage and impairs efficient recovery after IR‐induced DNA breaks. PHF6 is rapidly recruited to sites of laser‐induced DNA damage in a PARP‐dependent manner. PHF6 is required for efficient DNA repair through classical non‐homologous end joining. Graphical Abstract The PHD finger protein PHF6 is required for recovery from the DNA damage checkpoint and for viability after DSBs by promoting classical non‐homologous end joining.