BLM is required for faithful chromosome segregation and its localization defines a class of ultrafine anaphase bridges.
Mutations in BLM cause Bloom's syndrome, a disorder associated with cancer predisposition and chromosomal instability. We investigated whether BLM plays a role in ensuring the faithful chromosome segregation in human cells. We show that BLM-defective cells display a higher frequency of anaphase bridges and lagging chromatin than do isogenic corrected derivatives that eptopically express the BLM protein. In normal cells undergoing mitosis, BLM protein localizes to anaphase bridges, where it colocalizes with its cellular partners, topoisomerase IIIalpha and hRMI1 (BLAP75). Using BLM staining as a marker, we have identified a class of ultrafine DNA bridges in anaphase that are surprisingly prevalent in the anaphase population of normal human cells. These so-called BLM-DNA bridges, which also stain for the PICH protein, frequently link centromeric loci, and are present at an elevated frequency in cells lacking BLM. On the basis of these results, we propose that sister-chromatid disjunction is often incomplete in human cells even after the onset of anaphase. We present a model for the action of BLM in ensuring complete sister chromatid decatenation in anaphase.
Chan
Kok-Lung
KL
Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
North
Phillip S
PS
Hickson
Ian D
ID
D000251:Adenosine Triphosphatases / Q000172:deficiency / Q000378:metabolism*; D000705:Anaphase / Q000187:drug effects; D001816:Bloom Syndrome / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002503:Centromere / Q000187:drug effects / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D020090:Chromosome Segregation / Q000187:drug effects; D002877:Chromosomes, Human / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases / Q000172:deficiency / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D053484:RecQ Helicases; D059004:Topoisomerase I Inhibitors
D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; C501527:RMI1 protein, human; D059004:Topoisomerase I Inhibitors; D004247:DNA; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; C516980:ERCC6L protein, human; D053484:RecQ Helicases; D004264:DNA Topoisomerases, Type I