期刊
CELL
卷 174, 期 5, 页码 1127-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.07.011
关键词
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资金
- Intramural Research Program of the NIH
- Ellison Medical Foundation Senior Scholar in Aging Award [AG-SS-2633-11]
- Department of Defense [W81XWH-15-2-006, W81XWH-16-1-0599]
- Alex Lemonade Stand Foundation Award
- NIH Intramural FLEX Award
- American Cancer Society [PF-16-037-01-DMC]
- Ligue Nationale Contre le Cancer
- Association pour la Recherche sur le Cancer
- Fondation pour la Recherche Medicale [FRM DEI201512344404]
- Canceropole Ile-de France
- INCa [2016-1-PL-BIO-13-CNRS DR B-1]
- NATIONAL CANCER INSTITUTE [P30CA016056, ZIABC010959] Funding Source: NIH RePORTER
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.
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