Fused in sarcoma regulates DNA replication timing and progression

Fused in sarcoma (FUS) encodes a low complexity RNA-binding protein with diverse roles in transcriptional activation and RNA processing. While oncogenic fusions of FUS and transcription factor DNA-binding domains are associated with soft tissue sarcomas, dominant mutations in FUS cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. FUS has also been implicated in DNA double-strand break repair (DSBR) and genome maintenance. However, the extent to which FUS genome protection functions reflect direct participation in DNA repair complexes versus canonical roles in RNA processing is unknown. Here we describe new roles for FUS in DNA replication fork progression and genome-wide regulation of replication timing and demonstrate that FUS interacts with the DNA replication machinery. FUS-deficient cells exhibited alterations in the recruitment and retention of DSBR factors to DNA repair foci but were not hypersensitive to mechanistically diverse genotoxins or PARP inhibition. Finally, we show that FUS regulates the DNA replication-associated transcripts that may contribute to genome stability through alterations in protein function and gene dosage.