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

Anthony Tubbs, Sriram Sridharan, Niek van Wietmarschen, Yaakov Maman, Elsa Callen, Andre Stanlie, Wei Wu, Xia Wu, Amanda Day, Nancy Wong, Mianmian Yin, Andres Canela, Haiqing Fu, Christophe Redon, Steven C. Pruitt, Yan Jaszczyszyn, Mirit I. Aladjem, Peter D. Aplan, Olivier Hyrien, André Nussenzweig

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

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. Mammalian replication origins are fragile sites defined by poly-dA/dT stretches that are nucleosome free and devoid of the single-strand DNA-protecting protein RPA.

Original languageEnglish
Pages (from-to)1127-1142.e19
JournalCell
Volume174
Issue number5
DOIs
StatePublished - 23 Aug 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018

Keywords

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

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