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

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

Author information

1
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
2
Edinburgh Super-Resolution Imaging Consortium, Institute of Biological Chemistry, Biophysics, and Bioengineering, Heriot-Watt University, Edinburgh EH14 4AS, UK.
3
Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
4
Centre for Integrative Physiology, Edinburgh Medical School, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK.
5
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK. Electronic address: nick.gilbert@ed.ac.uk.

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

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PMID:
28622508
PMCID:
PMC5473940
DOI:
10.1016/j.cell.2017.05.029
[Indexed for MEDLINE]
Free PMC Article

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