Ó³»­´«Ã½

DNA double-strand breaks (DSB) are among the most deleterious forms of DNA damage and, if unresolved, result in DNA mutations and chromosomal aberrations that can cause disease, including cancer. Repair of DSBs by homologous recombination requires extensive nucleolytic digestion of DNA ends in a process known as DNA-end resection. In recent years, progress has been made in understanding how this process is initiated, but the later stages of this process-long-range DNA-end resection-are not well understood. Many questions remain in terms of how the DNA helicases and endonucleases that catalyse this process are regulated, a key step to avoiding spurious activity in the absence of breaks. The importance of DNA-end resection in human disease is highlighted by several human genetic syndromes that are caused by mutations or deficiencies in key proteins involved in this process. Here, using high-throughput microscopy coupled with a cDNA 'chromORFeome' library, we identified ZNF280A as an uncharacterized chromatin factor that is recruited to breaks and essential for DNA DSB repair. Lack of ZNF280A drives genomic instability and substantial sensitivity to DNA-damaging agents. Mechanistically, we demonstrate that ZNF280A promotes long-range DNA-end resection by facilitating the recruitment of the BLM-DNA2 helicase-nuclease complex to DNA DSB sites, enhancing efficiency of the enzymatic activity of this complex at DNA damage sites. ZNF280A is therefore essential for DNA-end resection and DNA repair by homologous recombination. Importantly, ZNF280A is hemizygously deleted in a human genetic condition, 22q11.2 distal deletion syndrome. Features of this condition include congenital heart disease, microcephaly, immune deficiency, developmental delay and cognitive deficits-features that are associated with other human syndromes caused by defects in genes involved in DNA repair. Remarkably, cells from individuals with a 22q11.2 distal deletion have defects in DNA-end resection and homologous recombination, resulting in increased incidence of genomic instability. These phenotypes are rescued by reintroduction of ZNF280A, providing evidence of defective DNA repair as a potential mechanistic explanation for several clinical features associated with this human condition.