Our data in fibroblasts obtained from familial ALS patients with the R521H and P525L FUS mutations, and iPSCs/motor neurons derived from these fibroblasts indicate that the two familial mutants, R521H and P525L, cause ligation defects by distinct mechanisms: the DNA damage-dependent association of nuclear FUS-R521H with PARP1 and XRCC1/LigIII is reduced, whereas FUS-P525L nuclear levels are low due to its aberrant cytoplasmic localization. This evidence concerns the gene XRCC1 and amyotrophic lateral sclerosis.