Figure 10.

Working model of FUS in replication progression and replication timing.A, based on FUS chromatin proteomics, FUS specifically interacts with POLδ but not POLε. Many replication-coupled single-strand break (SSB) repair factors (PCNA, FEN1, and PARP1) were also enriched with FUS on chromatin. From this, we speculate that FUS facilitates Okazaki fragment processing and PARP-dependent repair of single-strand gaps on the lagging strand (67). Defects in this pathway may contribute to reduced RF speed, RF restart defects, and micronucleus formation. B, speculative model for FUS-dependent RT. FUS undergoes phase separation where it may interact transiently recruits RNA polymerase II, potentially in cooperation with EWSR1 and TAF15. Phase-separated FUS complexes (shown in green circles) organize chromatin into topologically distinct domains (ERD, MRD, and LRD) that are replicated during early, mid, and late S-phase, respectively. The DNA fiber and micronuclei images were reused from Figure 3 for illustration purpose only. ERD, early replication domain; FEN1, flap endonuclease-1; FUS, fused in sarcoma; LRD, late replication domain; MRD, mid replication domain; PARP1, poly(ADP)-ribosyl (PAR) polymerase 1; PCNA, proliferating cell nuclear antigen; POLδ, polymerase δ; RF, replication fork.