Replication initiation and genome instability: A crossroads for DNA and RNA synthesis

Jacqueline Barlow, André Nussenzweig

Research output: Contribution to journalReview article

9 Scopus citations

Abstract

Nuclear DNA replication requires the concerted action of hundreds of proteins to efficiently unwind and duplicate the entire genome while also retaining epigenetic regulatory information. Initiation of DNA replication is tightly regulated, rapidly firing thousands of origins once the conditions to promote rapid and faithful replication are in place, and defects in replication initiation lead to proliferation defects, genome instability, and a range of developmental abnormalities. Interestingly, DNA replication in metazoans initiates in actively transcribed DNA, meaning that replication initiation occurs in DNA that is co-occupied with tens of thousands of poised and active RNA polymerase complexes. Active transcription can induce genome instability, particularly during DNA replication, as RNA polymerases can induce torsional stress, formation of secondary structures, and act as a physical barrier to other enzymes involved in DNA metabolism. Here we discuss the challenges facing mammalian DNA replication, their impact on genome instability, and the development of cancer.

Original languageEnglish (US)
Pages (from-to)4545-4559
Number of pages15
JournalCellular and Molecular Life Sciences
Volume71
Issue number23
DOIs
StatePublished - Oct 5 2014
Externally publishedYes

Keywords

  • DNA replication
  • Origin licensing
  • R loop
  • Replication stress
  • Transcription

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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