In light of the growing interest to target the balance between HR and NHEJ in cancer therapy and to modify the underlying mechanisms for improved genome editing, we envision that the dual switch mechanism from an H4K20me2–53BP1–dominated response in unreplicated chromatin to an H4K20me0–BRCA1–BARD1–dominated response in replicated nascent chromatin will be of relevance. This evidence concerns the gene BRCA1 and cancer.