SAF-A Regulates Interphase Chromosome Structure through Oligomerization with Chromatin-Associated RNAs

Cell. 2017 Jun 15;169(7):1214-1227.e18. doi: 10.1016/j.cell.2017.05.029.

Abstract

Higher eukaryotic chromosomes are organized into topologically constrained functional domains; however, the molecular mechanisms required to sustain these complex interphase chromatin structures are unknown. A stable matrix underpinning nuclear organization was hypothesized, but the idea was abandoned as more dynamic models of chromatin behavior became prevalent. Here, we report that scaffold attachment factor A (SAF-A), originally identified as a structural nuclear protein, interacts with chromatin-associated RNAs (caRNAs) via its RGG domain to regulate human interphase chromatin structures in a transcription-dependent manner. Mechanistically, this is dependent on SAF-A's AAA+ ATPase domain, which mediates cycles of protein oligomerization with caRNAs, in response to ATP binding and hydrolysis. SAF-A oligomerization decompacts large-scale chromatin structure while SAF-A loss or monomerization promotes aberrant chromosome folding and accumulation of genome damage. Our results show that SAF-A and caRNAs form a dynamic, transcriptionally responsive chromatin mesh that organizes large-scale chromosome structures and protects the genome from instability.

Keywords: AAA(+) ATPases; SAF-A; chromatin; chromatin compaction; chromatin-associated RNAs; chromosome stability; hnRNPU; nuclear architecture; transcription.

MeSH terms

  • Amino Acid Sequence
  • Chromatin
  • Chromosomes / metabolism*
  • Genomic Instability*
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoprotein U / chemistry
  • Heterogeneous-Nuclear Ribonucleoprotein U / metabolism*
  • Humans
  • Interphase
  • Models, Molecular
  • RNA, Small Nuclear / metabolism*
  • Sequence Alignment
  • Transcription, Genetic

Substances

  • Chromatin
  • Heterogeneous-Nuclear Ribonucleoprotein U
  • RNA, Small Nuclear
  • SAF-A protein, human