Selectivity of ORC binding sites and the relation to replication timing, fragile sites, and deletions in cancers

Benoit Miotto, Zhe Ji, Kevin Struhl*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

Abstract

The origin recognition complex (ORC) binds sites from which DNA replication is initiated. We address ORC binding selectivity in vivo by mapping ∼52,000 ORC2 binding sites throughout the human genome. The ORC binding profile is broader than those of sequence-specific transcription factors, suggesting that ORC is not bound or recruited to specific DNA sequences. Instead, ORC binds nonspecifically to open (DNase I-hypersensitive) regions containing active chromatin marks such as H3 acetylation and H3K4 methylation. ORC sites in early and late replicating regions have similar properties, but there are far more ORC sites in early replicating regions. This suggests that replication timing is due primarily to ORC density and stochastic firing of origins. Computational simulation of stochastic firing from identified ORC sites is in accord with replication timing data. Large genomic regions with a paucity of ORC sites are strongly associated with common fragile sites and recurrent deletions in cancers.We suggest that replication origins, replication timing, and replication-dependent chromosome breaks are determined primarily by the genomic distribution of activator proteins at enhancers and promoters. These activators recruit nucleosome-modifying complexes to create the appropriate chromatin structure that allows ORC binding and subsequent origin firing.

Original languageEnglish (US)
Pages (from-to)E4810-E4819
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number33
DOIs
StatePublished - Aug 16 2016

Funding

We thank Michael Snyder, Mark Gerstein, and members of their laboratories for DNA sequencing and generating the raw sequencing files; Johannes Walter and Steve Bell for useful discussions; and Nick Rhind for suggesting why ORC sites might be more frequent than SNS sites in early, but not late, replicating regions. The ORC2 ChIP-sequencing data were generated as part of the ENCODE Project Consortium. This work was supported by National Institutes of Health Grants GM30186 and HG4458 (to K.S.).

Keywords

  • Chromatin
  • DNA replication
  • ORC
  • Replication origins
  • Replication timing

ASJC Scopus subject areas

  • General

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