Replication stress induces sister-chromatid bridging at fragile site loci in mitosis
By Kok-Lung Chan, T. Palmai-Pallag, S. Ying, Ian D. Hickson. Nature Cell Biology, 2009
600 citations recorded by the source corpus.
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.
Subfields: Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/b732ae056bd16cd0c1e403527f40c35468c9f1f4
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Citations in the corpus
- More than just a focus: The chromatin response to DNA damage and its role in genome integrity maintenance (2011, background): “, or if they escape breakage, their entangled DNA can be resolved by the DNA decatenating activity of the BLM complex confined to ultrafine DNA bridges between anaphase chromosome”
- Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication (2009, unknown): “…of TRF1 null cells with ATR shRNA but not by aphidicolin treatment or absence of DNA ligase IV (lig4 (cid:2) / (cid:2) ). below, it is tempting to speculate that the sister telomere associations represent the recently described sister chromatid bridges at fragile sites (Chan et al., 2009).”
- Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. (2011, background): “Both FA and BLM are required for efficient resolution of these DNA linkages which if left unresolved would give rise to formation of NPB and MN during mitosis (46,49).”
- DNA replication stress as a hallmark of cancer. (2015, background): “Thus, any form of DNA replication stress that slows down replication could result in cells entering mitosis with the CFSs not having been fully replicated (123).”