Expanded CAG Repeats Activate the DNA Damage Checkpoint Pathway

• DOI: 10.1016/j.molcel.2004.06.034
• Publication Date: 2004-07-23T19:10:35Z
• Authors: Mayurika Lahiri; Tanya L Gustafson; Elizabeth R Majors; Catherine H Freud...
• Keywords: 0303 health sciences; Saccharomyces cerevisiae Proteins; Cell Cycle; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Cell Cycle Proteins; Cell Biology; Saccharomyces cerevisiae; Protein Serine-Threonine Kinases; DNA-Binding Proteins; Checkpoint Kinase 2; 03 medical and health sciences; Chromosomal Instability; Trinucleotide Repeat Expansion; Molecular Biology; DNA Damage; Sequence Deletion; Signal Transduction

Trinucleotide repeats (TNRs) are sequences whose expansion causes several genetic diseases and chromosome breakage. We report a novel finding that expanded CAG repeats activate the DNA damage response. Mutations in yeast MEC1, RAD9, or RAD53 genes result in increased rates of fragility of a CAG repeat tract while single or double deletions of RAD17 or RAD24 have only a modest effect on TNR fragility, indicating that signaling down the Rad9 pathway and not the Rad17-Rad24 pathway plays a major role in sensing and repairing CAG-tract breaks. Deletion of CHK1 had no effect on CAG fragility, suggesting that a Chk1-mediated G2 arrest is not required for TNR repair. Absence of Mec1, Ddc2, Rad17, Rad24, or Rad53 also gives rise to increased frequency of CAG repeat contractions, indicating that components of the checkpoint machinery play an active role in the maintenance of both chromosomal integrity and repeat stability at expanded CAG sequences.