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Engineering translocations with delayed replication: evidence for cis control of chromosome replication timing
Kevin S Breger1, Leslie Smith, Mathew J Thayer
1Division of Molecular Medicine, Oregon Health and Science University, 3181 S.W.Sam Jackson Park Road, Portland, OR 97239, USA.
Human Molecular Genetics
|August 24, 2005
Summary
Certain chromosome rearrangements cause a delay in replication timing and condensation, leading to genomic instability. This study engineered chromosomes with this phenotype, revealing a cis-acting mechanism contributing to cancer and radiation-induced instability.
Area of Science:
- Cell Biology
- Genetics
- Cancer Research
Background:
- Chromosome rearrangements are hallmarks of cancer and radiation damage.
- A subset of these rearrangements exhibit a chromosome-wide delay in replication timing (DRT) and delay in mitotic chromosome condensation (DMC).
Purpose of the Study:
- To engineer chromosomes with the DRT/DMC phenotype.
- To investigate the underlying mechanisms and consequences of DRT/DMC.
Main Methods:
- Chromosome engineering strategy to generate DRT/DMC chromosomes.
- Induction of inter-chromosomal translocations using site-specific recombination (Cre) or non-homologous end joining (NHEJ) with I-Sce1.
- Analysis of gross chromosomal rearrangements in engineered chromosomes.
Main Results:
- Approximately 10% of induced translocations resulted in DRT/DMC.
- The DRT/DMC phenotype was observed on specific derivative chromosomes of balanced translocations.
- Engineered DRT/DMC chromosomes showed an increased rate of gross chromosomal rearrangements.
Conclusions:
- The DRT/DMC phenotype is regulated by a cis-acting mechanism, not stochastic damage response.
- DRT/DMC is a significant contributor to genomic instability in cancer and after radiation exposure.