Replication stress induces sister-chromatid bridging at fragile site loci in mitosis.
Several inherited syndromes in humans are associated with cancer predisposition. The gene products defective in two of these disorders, BLM (a helicase defective in Bloom's syndrome) and FANC A-N (defective in Fanconi anaemia), associate in a multienzyme complex called BRAFT. How these proteins suppress tumorigenesis remains unclear, although both conditions are associated with chromosome instability. Here we show that the Fanconi anaemia proteins FANCD2 and FANCI specifically associate with common fragile site loci irrespective of whether the chromosome is broken. Unexpectedly, these loci are frequently interlinked through BLM-associated ultra-fine DNA bridges (UFBs) even as cells traverse mitosis. Similarly to fragile site expression, fragile site bridging is induced after partial inhibition of DNA replication. We propose that, after replication stress, sister chromatids are interlinked by replication intermediates primarily at genetic loci with intrinsic replication difficulties, such as fragile sites. In Bloom's syndrome cells, inefficient resolution of DNA linkages at fragile sites gives rise to increased numbers of anaphase UFBs and micronuclei containing fragile site DNA. Our data have general implications concerning the contribution of fragile site loci to chromosomal instability and tumorigenesis.
Chan
Kok Lung
KL
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Palmai-Pallag
Timea
T
Ying
Songmin
S
Hickson
Ian D
ID
D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000378:metabolism; D001816:Bloom Syndrome / Q000235:genetics; D002460:Cell Line; D002842:Chromatids / Q000235:genetics / Q000378:metabolism*; D043283:Chromosome Fragile Sites; D002874:Chromosome Mapping; D004261:DNA Replication; D005199:Fanconi Anemia / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008938:Mitosis / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation; D034622:RNA Interference; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009363:Neoplasm Proteins; D053484:RecQ Helicases; D000099170:Bis(5'-adenosyl)triphosphatase; C519921:FANCI protein, human; C097151:Bloom syndrome protein