Figure 1: The involvement of FUS in transcription and DNA damage repair. (1) Transcription associated DNA can arise from abortive TOP1 functioning, which is mimicked by Camptothecin treatment blocking re-ligation. Under this condition a relocation of FUS normally bound to the C-terminal domain of RNA polymerase II to the nucleolus occurs for an unknown reason (Martinez-Macias et al., 2019). (2) Its importance in the DSB repair by allowing recruitment of HDAC1 and other DSB repair factors was found by examining primary neurons and U2OS cells, which was impaired by FUS mutations (Wang et al., 2013). Furthermore, upon induction of DNA damage FUS was demonstrated to be phosphorylated by DNA-PK, which is a member of the classical NHEJ pathway. This N-terminal phosphorylation in its low complexity domain resulted in an egress from the nucleus to the cytoplasm. (3) In human neurons FUS acts downstream of PARP1 and tethers the XRCC1/LIG3 complex to the SSB site enabling proper ligation of the nicks. Of note, SSB nick processing is essential and for instance ensured by the enzymes TDP1, APTX and PNKP. Mutations in these were associated with the neurological syndromes SCAN1, ataxia oculomotor apraxia 1 and MCSZ, respectively. APTX: Aprataxin; DNA-PK: DNA-dependent protein kinase; DSB: double strand break; FUS: fused in sarcoma; HDAC1: histone deacetylase 1; LIG3: DNA ligase 3; MCSZ: microcephaly, early-onset, intractable seizures and developmental delay; NHEJ: non-homologous end joining; PARP1: poly [ADP-ribose] polymerase 1; PNKP: polynucleotide kinase 3′-phosphatase; SCAN1: spinocerebellar ataxia with axonal neuropathy type 1; SSB: single strand break; TDP1: tyrosyl-DNA phosphodiesterase 1; TOP1: topoisomerase 1; XRCC1: X-ray repair cross-complementing protein 1.