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Publication Detail

Title: Fused in sarcoma regulates DNA replication timing and kinetics.

Authors: Jia, Weiyan; Kim, Sang Hwa; Scalf, Mark A; Tonzi, Peter; Millikin, Robert J; Guns, William M; Liu, Lu; Mastrocola, Adam S; Smith, Lloyd M; Huang, Tony T; Tibbetts, Randal S

Published In J Biol Chem, (2021 09)

Abstract: Fused in sarcoma (FUS) encodes an RNA-binding protein with diverse roles in transcriptional activation and RNA splicing. While oncogenic fusions of FUS and transcription factor DNA-binding domains are associated with soft tissue sarcomas, dominant mutations in FUS can cause amyotrophic lateral sclerosis. FUS has also been implicated in genome maintenance. However, the underlying mechanisms of its actions in genome stability are unknown. Here, we applied gene editing, functional reconstitution, and integrated proteomics and transcriptomics to illuminate roles for FUS in DNA replication and repair. Consistent with a supportive role in DNA double-strand break repair, FUS-deficient cells exhibited subtle alterations in the recruitment and retention of double-strand break-associated factors, including 53BP1 and BRCA1. FUS-/- cells also exhibited reduced proliferative potential that correlated with reduced speed of replication fork progression, diminished loading of prereplication complexes, enhanced micronucleus formation, and attenuated expression and splicing of S-phase-associated genes. Finally, FUS-deficient cells exhibited genome-wide alterations in DNA replication timing that were reversed upon re-expression of FUS complementary DNA. We also showed that FUS-dependent replication domains were enriched in transcriptionally active chromatin and that FUS was required for the timely replication of transcriptionally active DNA. These findings suggest that alterations in DNA replication kinetics and programming contribute to genome instability and functional defects in FUS-deficient cells.

PubMed ID: 34375640 Exiting the NIEHS site

MeSH Terms: BRCA1 Protein/genetics; BRCA1 Protein/metabolism; Cell Proliferation; DNA Breaks, Double-Stranded; DNA Repair; DNA Replication Timing*; Humans; Kinetics; RNA-Binding Protein FUS/genetics; RNA-Binding Protein FUS/metabolism*; Sarcoma/genetics*; Sarcoma/metabolism*; Tumor Suppressor p53-Binding Protein 1/genetics; Tumor Suppressor p53-Binding Protein 1/metabolism

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