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DNA breaks promote genomic instability by impeding proper chromosome segregation
Julia A Kaye1, Justine A Melo, Stephanie K Cheung
1Cancer Research Institute, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94115, USA.
Current Biology : CB
|December 14, 2004
Summary
Broken chromosome ends remain associated during mitosis, leading to missegregation of fragments. This DNA break-induced missegregation offers a new mechanism for loss of heterozygosity preceding tumorigenesis.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Unrepaired DNA double-stranded breaks (DSBs) can lead to chromosome loss.
- Previous studies showed broken chromosome ends remain associated.
- This study investigates the machinery and behavior of broken chromosomes during mitosis.
Purpose of the Study:
- To examine the machinery holding broken chromosome ends together.
- To explore the behavior of broken chromosomes during mitotic progression.
- To understand the mechanisms of chromosome missegregation and loss of heterozygosity.
Main Methods:
- Utilized GFP-localized arrays flanking an HO endonuclease site in yeast.
- Employed checkpoint arrest in metaphase to study chromosome end association.
- Conducted pedigree analysis to track repair and segregation of broken chromosomes.
Main Results:
- Chromosome end association is partially dependent on Rad50 and Rad52.
- Cells adapted to checkpoint arrest, resuming mitosis and segregating broken chromosomes.
- Acentric fragments cosegregated into single daughter cells 95% of the time.
- Postmitotic repair occurred in either mother or daughter cells, rarely both.
Conclusions:
- An intrachromosomal association holds broken sister chromatid halves together in metaphase.
- An interchromosomal force tethers broken sister chromatids, promoting missegregation.
- DNA break-induced missegregation of both acentric and centric fragments offers a novel mechanism for loss of heterozygosity in tumorigenesis.