Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability

Cell Rep. 2019 Aug 6;28(6):1551-1563.e7. doi: 10.1016/j.celrep.2019.07.010.


THO/TREX is a conserved complex with a role in messenger ribonucleoprotein biogenesis that links gene expression and genome instability. Here, we show that human THO interacts with MFAP1 (microfibrillar-associated protein 1), a spliceosome-associated factor. Interestingly, MFAP1 depletion impairs cell proliferation and genome integrity, increasing γH2AX foci and DNA breaks. This phenotype is not dependent on either transcription or RNA-DNA hybrids. Mutations in the yeast orthologous gene SPP381 cause similar transcription-independent genome instability, supporting a conserved role. MFAP1 depletion has a wide effect on splicing and gene expression in human cells, determined by transcriptome analyses. MFAP1 depletion affects a number of DNA damage response (DDR) genes, which supports an indirect role of MFAP1 on genome integrity. Our work defines a functional interaction between THO and RNA processing and argues that splicing factors may contribute to genome integrity indirectly by regulating the expression of DDR genes rather than by a direct role.

Keywords: MFAP1/SPP381; THO complex; alternative splicing; genome instability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Cell Cycle
  • Cell Proliferation
  • Contractile Proteins / metabolism*
  • DNA-Binding Proteins / metabolism
  • Extracellular Matrix Proteins / metabolism*
  • Gene Expression Regulation
  • Genome, Human
  • Genomic Instability*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • R-Loop Structures*
  • RNA Processing, Post-Transcriptional
  • RNA Splicing Factors / metabolism*
  • RNA-Binding Proteins / metabolism
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / metabolism
  • Spliceosomes / metabolism


  • Contractile Proteins
  • DNA-Binding Proteins
  • Extracellular Matrix Proteins
  • RNA Splicing Factors
  • RNA-Binding Proteins
  • Saccharomyces cerevisiae Proteins
  • THOC1 protein, human
  • microfibrillar protein