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Cell. 2018 Aug 23;174(5):1127-1142.e19. doi: 10.1016/j.cell.2018.07.011. Epub 2018 Aug 2.

Dual Roles of Poly(dA:dT) Tracts in Replication Initiation and Fork Collapse.

Author information

1
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
2
IBENS, Département de Biologie, Ecole Normale Supérieure, CNRS, Inserm, PSL Research University, 75005 Paris, France.
3
Genetics Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
4
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, NIH, Bethesda, MD, USA.
5
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
6
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
7
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address: andre_nussenzweig@nih.gov.

Abstract

Replication origins, fragile sites, and rDNA have been implicated as sources of chromosomal instability. However, the defining genomic features of replication origins and fragile sites are among the least understood elements of eukaryote genomes. Here, we map sites of replication initiation and breakage in primary cells at high resolution. We find that replication initiates between transcribed genes within nucleosome-depleted structures established by long asymmetrical poly(dA:dT) tracts flanking the initiation site. Paradoxically, long (>20 bp) (dA:dT) tracts are also preferential sites of polar replication fork stalling and collapse within early-replicating fragile sites (ERFSs) and late-replicating common fragile sites (CFSs) and at the rDNA replication fork barrier. Poly(dA:dT) sequences are fragile because long single-strand poly(dA) stretches at the replication fork are unprotected by the replication protein A (RPA). We propose that the evolutionary expansion of poly(dA:dT) tracts in eukaryotic genomes promotes replication initiation, but at the cost of chromosome fragility.

KEYWORDS:

DNA breaks; fragile sites; genome instability; poly(dA:dT) tracts; replication fork barrier; replication origins; replication stress; ribosomal DNA

Comment in

PMID:
30078706
PMCID:
PMC6591735
DOI:
10.1016/j.cell.2018.07.011
[Indexed for MEDLINE]
Free PMC Article

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