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

Ryu-Suke Nozawa,Lora Boteva,Dinesh C Soares,Catherine Naughton,Alison R Dun,Adam Buckle,Bernard Ramsahoye,Peter C Bruton,Rebecca S Saleeb,Maria Arnedo,Bill Hill,Rory R Duncan,Sutherland K Maciver,Nick Gilbert

doi:10.1016/j.cell.2017.05.029

Ryu-Suke Nozawa, Lora Boteva + Show 12 more

Open Access

https://doi.org/10.1016/j.cell.2017.05.029

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Abstract

SummaryHigher 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.

Highlights

Mammalian interphase chromosomes are organized into topologically constrained chromatin domains (Belmont et al, 1989), which are responsive to transcription (Naughton et al, 2013) and local gene density (Goetze et al, 2007)
We suggest that scaffold attachment factor A (SAF-A) interacts with chromatin-associated RNAs (caRNAs) to form a chromatin mesh (Nozawa and Gilbert, 2014), and unlike the historical concept of a nuclear matrix, is highly responsive to ongoing transcription and can undergo dynamic cycles of assembly and disassembly
SAF-A’s abundance, localization, and structural characteristics suggest it may play a role in organizing nuclear architecture (Hall and Lawrence, 2016)

Summary

Introduction

Mammalian interphase chromosomes are organized into topologically constrained chromatin domains (Belmont et al, 1989), which are responsive to transcription (Naughton et al, 2013) and local gene density (Goetze et al, 2007). We suggested that transcription and topoisomerase activities, that occur at the gene level, alter local topology to form supercoiling domains (Naughton et al, 2013) and these correspond to structures seen by Hi-C (Rao et al, 2014). It is unclear, how these processes could impact on large-scale chromatin structures. Recent studies have been unable to find specific species of RNA, similar to XIST, which could regulate large-scale chromatin structure, suggesting instead that diverse caRNAs transiently interact with chromatin, forming a dynamic compartment

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