Taken together with PARPi hyper-sensitization and minimal predicted toxicity of removing or inhibiting ALC1, our work raises the possibility that selective small-molecule ALC1 inhibitors or degraders could provide an important therapeutic option in HRD- or ATM-deficient cancers, either alone or as a means to enhance PARPi sensitivity. Here, CHD1L is linked to hypoparathyroidism-retardation-dysmorphism syndrome.