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

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 p...

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Bibliographic Details
Published in:Cellular and molecular life sciences : CMLS 2014-12, Vol.71 (23), p.4545-4559
Main Authors: Barlow, Jacqueline H, Nussenzweig, André
Format: Article
Language:English
Subjects:
abnormal development
Animalia
Animals
Barriers
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cell Biology
Deoxyribonucleic acid
DNA
DNA - genetics
DNA Replication
DNA-directed RNA polymerase
Enzymes
epigenetics
Genomic Instability
Genomics
Humans
Life Sciences
mammals
metabolism
Metazoa
Multi-Author Review
Neoplasms - genetics
nuclear genome
proteins
Replication Origin
Ribonucleic acid
RNA
RNA - genetics
transcription (genetics)
Transcription factors
Transcription, Genetic
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Summary: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.
ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-014-1721-1