Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations
Kihoon Lee1, Yu Zhang, Sang Eun Lee
1Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA.
Abstract:
Chromosome translocations are frequently associated with many types of blood-related cancers and childhood sarcomas. Detection of chromosome translocations assists in diagnosis, treatment and prognosis of these diseases; however, despite their importance to such diseases, the molecular mechanisms leading to chromosome translocations are not well understood. The available evidence indicates a role for non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs) in their origin. Here we develop a yeast-based system that induces a reciprocal chromosome translocation by formation and ligation of breaks on two different chromosomes. We show that interchromosomal end joining is efficiently suppressed by the Tel1- and Mre11-Rad50-Xrs2-dependent pathway; this is distinct from the role of Tel1 in telomeric integrity and from Mec1- and Tel1-dependent checkpoint controls. Suppression of DSB-induced chromosome translocations depends on the kinase activity of Tel1 and Dun1, and the damage-induced phosphorylation of Sae2 and histone H2AX proteins. Tel1- and Sae2-dependent tethering and promotion of 5' to 3' degradation of broken chromosome ends discourage error-prone NHEJ and interchromosomal NHEJ, preserving chromosome integrity on DNA damage. Our results indicate that, like human ATM, Tel1 serves as a key regulator for chromosome integrity in the pathway that reduces the risk for DSB-induced chromosome translocations, and are probably pertinent to the oncogenic chromosome translocations in ATM-deficient cells.
Insights
A yeast system reveals how Tel1 and Sae2 prevent DNA double-strand breaks from causing cancer-linked chromosome translocations by degrading broken DNA ends. This pathway preserves chromosome integrity and reduces translocation risk.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Chromosome translocations are hallmarks of various cancers, including blood cancers and sarcomas.
- The precise molecular mechanisms driving chromosome translocations remain incompletely understood.
- Non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs) is implicated in translocation formation.
Purpose of the Study:
- To investigate the molecular pathways that suppress chromosome translocations.
- To elucidate the role of the Tel1 pathway in maintaining chromosome integrity following DNA damage.
- To understand how specific proteins regulate the repair of DNA double-strand breaks.
Main Methods:
- Development of a yeast model system to induce reciprocal chromosome translocations.
- Analysis of gene dependencies, including Tel1, Mre11-Rad50-Xrs2, Mec1, and Dun1.
- Assessment of protein phosphorylation, specifically Sae2 and histone H2AX.
- Investigation of DNA end tethering and degradation processes.
Main Results:
- Interchromosomal end joining is suppressed by a Tel1- and Mre11-Rad50-Xrs2-dependent pathway.
- Suppression of translocations requires the kinase activity of Tel1 and Dun1, and phosphorylation of Sae2 and H2AX.
- Tel1 and Sae2 promote DNA end tethering and 5' to 3' degradation, inhibiting error-prone NHEJ.
- This pathway is distinct from telomeric functions and checkpoint controls of Tel1.
Conclusions:
- Tel1 acts as a crucial regulator of chromosome integrity, similar to human ATM.
- The identified pathway actively reduces the risk of DSB-induced chromosome translocations.
- Findings are relevant to understanding oncogenic translocations in ATM-deficient cancers.
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