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

Jacqueline Barlow, André Nussenzweig

Research output: Contribution to journalReview article

8 Citations (Scopus)

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

Fingerprint

Genomic Instability
DNA Replication
RNA
DNA
DNA-Directed RNA Polymerases
Architectural Accessibility
Epigenomics
Genome
Enzymes
Neoplasms
Proteins

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

Cite this

Replication initiation and genome instability : A crossroads for DNA and RNA synthesis. / Barlow, Jacqueline; Nussenzweig, André.

In: Cellular and Molecular Life Sciences, Vol. 71, No. 23, 05.10.2014, p. 4545-4559.

Research output: Contribution to journalReview article

@article{590e7447582b48789abc76ed309ced7d,
title = "Replication initiation and genome instability: A crossroads for DNA and RNA synthesis",
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.",
keywords = "DNA replication, Origin licensing, R loop, Replication stress, Transcription",
author = "Jacqueline Barlow and Andr{\'e} Nussenzweig",
year = "2014",
month = "10",
day = "5",
doi = "10.1007/s00018-014-1721-1",
language = "English (US)",
volume = "71",
pages = "4545--4559",
journal = "Cellular and Molecular Life Sciences",
issn = "1420-682X",
publisher = "Birkhauser Verlag Basel",
number = "23",

}

TY - JOUR

T1 - Replication initiation and genome instability

T2 - A crossroads for DNA and RNA synthesis

AU - Barlow, Jacqueline

AU - Nussenzweig, André

PY - 2014/10/5

Y1 - 2014/10/5

N2 - 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.

AB - 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.

KW - DNA replication

KW - Origin licensing

KW - R loop

KW - Replication stress

KW - Transcription

UR - http://www.scopus.com/inward/record.url?scp=84922007776&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922007776&partnerID=8YFLogxK

U2 - 10.1007/s00018-014-1721-1

DO - 10.1007/s00018-014-1721-1

M3 - Review article

C2 - 25238783

AN - SCOPUS:84922007776

VL - 71

SP - 4545

EP - 4559

JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

SN - 1420-682X

IS - 23

ER -