Dual Roles of Poly(dA:dT) Tracts in Replication Initiation and Fork Collapse.
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.
['Tubbs|Anthony|A|', 'Sridharan|Sriram|S|', 'van Wietmarschen|Niek|N|', 'Maman|Yaakov|Y|', 'Callen|Elsa|E|', 'Stanlie|Andre|A|', 'Wu|Wei|W|', 'Wu|Xia|X|', 'Day|Amanda|A|', 'Wong|Nancy|N|', 'Yin|Mianmian|M|', 'Canela|Andres|A|', 'Fu|Haiqing|H|', 'Redon|Christophe|C|', 'Pruitt|Steven C|SC|', 'Jaszczyszyn|Yan|Y|', 'Aladjem|Mirit I|MI|', 'Aplan|Peter D|PD|', 'Hyrien|Olivier|O|', 'Nussenzweig|André|A|']
D020816:Amino Acid Motifs D000818:Animals D002460:Cell Line D047369:Chromatin Immunoprecipitation D043171:Chromosomal Instability D043283:Chromosome Fragile Sites D002873:Chromosome Fragility D004261:DNA Replication D004275:DNA, Ribosomal D005260:Female D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009707:Nucleosomes D011067:Poly dA-dT D018741:Replication Origin D012441:Saccharomyces cerevisiae D012568:Schizosaccharomyces D024363:Transcription Initiation Site D014158:Transcription, Genetic
poly(dA:dT) tracts replication origins fragile sites replication fork barrier DNA breaks genome instability replication stress ribosomal DNA