SAF-A promotes origin licensing and replication fork progression to ensure robust DNA replication

Caitlin Connolly, Saori Takahashi, Hisashi Miura, Ichiro Hiratani, Nick Gilbert, Anne Donaldson, Shin-ichiro Hiraga* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The organisation of chromatin is closely intertwined with biological activities of
chromosome domains, including transcription and DNA replication status. Scaffold attachment factor A (SAF-A), also known as Heteronuclear Ribonucleoprotein Protein U (HNRNPU), contributes to the formation of open chromatin structure. Here we demonstrate that SAF-A promotes the normal progression of DNA replication, and enables resumption of replication after inhibition. We report that cells depleted for SAF-A show reduced origin licensing in G1 phase, and consequently reduced origin activation frequency in S phase. Replication forks also progress less consistently in cells depleted for SAF-A, contributing to reduced DNA synthesis rate. Single-cell replication timing analysis revealed two distinct effects of SAF-A depletion: first, the boundaries between early- and late-replicating domains become more blurred; and second, SAF-A depletion causes replication timing changes that tend to bring regions of discordant domain compartmentalisation and replication timing into concordance. Associated with these defects, SAF-A-depleted cells show elevated g-H2AX formation and tend to enter quiescence. Overall we find that SAF-A
protein promotes robust DNA replication to ensure continuing cell proliferation.
Original languageEnglish
Number of pages60
JournalJournal of Cell Science
Early online date10 Dec 2021
DOIs
Publication statusE-pub ahead of print - 10 Dec 2021

Keywords

  • DNA replication
  • Chromatin
  • Replication stress

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