Replication Stress Induces Sister-chromatid Bridging at Fragile Site Loci in Mitosis

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2009 May 26

PMID 19465922

Citations 376

Authors

Kok Lung Chan

Timea Palmai-Pallag

Songmin Ying

Ian D Hickson

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The interplay of the translocase activity and protein recruitment function of PICH in ultrafine anaphase bridge resolution and genomic stability.

Kong N, Chen K, Chanboonyasitt P, Jiang H, Wong K, Ma H Nucleic Acids Res. 2024; 53(3).

PMID: 39704103 PMC: 11797016. DOI: 10.1093/nar/gkae1249.

repeat expansion creates the unstable folate-sensitive fragile site FRA9A.

Mirceta M, Schmidt M, Shum N, Prasolava T, Meikle B, Lanni S NAR Mol Med. 2024; 1(4):ugae019.

PMID: 39669124 PMC: 11632612. DOI: 10.1093/narmme/ugae019.

RAD52 and ERCC6L/PICH have a compensatory relationship for genome stability in mitosis.

Osia B, Merkell A, Lopezcolorado F, Ping X, Stark J PLoS Genet. 2024; 20(11):e1011479.

PMID: 39561207 PMC: 11614213. DOI: 10.1371/journal.pgen.1011479.

53BP1-the 'Pandora's box' of genome integrity.

Kilgas S, Swift M, Chowdhury D DNA Repair (Amst). 2024; 144:103779.

PMID: 39476547 PMC: 11611608. DOI: 10.1016/j.dnarep.2024.103779.

p53-dependent crosstalk between DNA replication integrity and redox metabolism mediated through a NRF2-PARP1 axis.

Elfar G, Aning O, Ngai T, Yeo P, Chan J, Sim S Nucleic Acids Res. 2024; 52(20):12351-12377.

PMID: 39315696 PMC: 11551750. DOI: 10.1093/nar/gkae811.

References

Wang L, Schwarzbraun T, Speicher M, Nigg E . Persistence of DNA threads in human anaphase cells suggests late completion of sister chromatid decatenation. Chromosoma. 2007; 117(2):123-35. PMC: 2755729. DOI: 10.1007/s00412-007-0131-7. View

Casper A, Nghiem P, Arlt M, Glover T . ATR regulates fragile site stability. Cell. 2003; 111(6):779-89. DOI: 10.1016/s0092-8674(02)01113-3. View

Chan K, North P, Hickson I . BLM is required for faithful chromosome segregation and its localization defines a class of ultrafine anaphase bridges. EMBO J. 2007; 26(14):3397-409. PMC: 1933408. DOI: 10.1038/sj.emboj.7601777. View

Schwartz M, Zlotorynski E, Goldberg M, Ozeri E, Rahat A, le Sage C . Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability. Genes Dev. 2005; 19(22):2715-26. PMC: 1283964. DOI: 10.1101/gad.340905. View

Hirota T, Gerlich D, Koch B, Ellenberg J, Peters J . Distinct functions of condensin I and II in mitotic chromosome assembly. J Cell Sci. 2004; 117(Pt 26):6435-45. DOI: 10.1242/jcs.01604. View

Durkin S, Ragland R, Arlt M, Mulle J, Warren S, Glover T . Replication stress induces tumor-like microdeletions in FHIT/FRA3B. Proc Natl Acad Sci U S A. 2007; 105(1):246-51. PMC: 2224195. DOI: 10.1073/pnas.0708097105. View

German J . Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine (Baltimore). 1993; 72(6):393-406. View

Durkin S, Glover T . Chromosome fragile sites. Annu Rev Genet. 2007; 41:169-92. DOI: 10.1146/annurev.genet.41.042007.165900. View

Meetei A, Sechi S, Wallisch M, Yang D, Young M, Joenje H . A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Mol Cell Biol. 2003; 23(10):3417-26. PMC: 164758. DOI: 10.1128/MCB.23.10.3417-3426.2003. View

10.

Taniguchi T, Garcia-Higuera I, Xu B, Andreassen P, Gregory R, Kim S . Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell. 2002; 109(4):459-72. DOI: 10.1016/s0092-8674(02)00747-x. View

11.

Baumann C, Korner R, Hofmann K, Nigg E . PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell. 2007; 128(1):101-14. DOI: 10.1016/j.cell.2006.11.041. View

12.

Mankouri H, Hickson I . The RecQ helicase-topoisomerase III-Rmi1 complex: a DNA structure-specific 'dissolvasome'?. Trends Biochem Sci. 2007; 32(12):538-46. DOI: 10.1016/j.tibs.2007.09.009. View

13.

Losada A, Hirano T . Dynamic molecular linkers of the genome: the first decade of SMC proteins. Genes Dev. 2005; 19(11):1269-87. DOI: 10.1101/gad.1320505. View

14.

Arlt M, Casper A, Glover T . Common fragile sites. Cytogenet Genome Res. 2003; 100(1-4):92-100. DOI: 10.1159/000072843. View

15.

Ellis N, Groden J, Ye T, Straughen J, Lennon D, Ciocci S . The Bloom's syndrome gene product is homologous to RecQ helicases. Cell. 1995; 83(4):655-66. DOI: 10.1016/0092-8674(95)90105-1. View

16.

Wang W . Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet. 2007; 8(10):735-48. DOI: 10.1038/nrg2159. View