ATR regulates fragile site stability.
Conditions that partially inhibit DNA replication induce expression of common fragile sites. These sites form gaps and breaks on metaphase chromosomes and are deleted and rearranged in many tumors. Yet, the mechanism of fragile site expression has been elusive. We demonstrate that the replication checkpoint kinase ATR, but not ATM, is critical for maintenance of fragile site stability. ATR deficiency results in fragile site expression with and without addition of replication inhibitors. Thus, we propose that fragile sites are unreplicated chromosomal regions resulting from stalled forks that escape the ATR replication checkpoint. These findings have important implications for understanding both the mechanism of fragile site instability and the consequences of stalled replication in mammalian cells.
Casper
Anne M
AM
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
Nghiem
Paul
P
Arlt
Martin F
MF
Glover
Thomas W
TW
D015075:2-Aminopurine / Q000494:pharmacology; D000963:Antimetabolites / Q000494:pharmacology; D016590:Aphidicolin / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D002110:Caffeine / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000502:physiology*; D002478:Cells, Cultured; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D002875:Chromosomes / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008677:Metaphase; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D000963:Antimetabolites; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010726:Phosphodiesterase Inhibitors; D025521:Tumor Suppressor Proteins; D016590:Aphidicolin; D002110:Caffeine; D015075:2-Aminopurine; D004247:DNA; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases