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Localization to the Nuclear Pore Complex is Required to Prevent Trinucleotide Repeat Instability
Author(s) -
Su Xiaofeng,
Dion Vincent,
Gasser Susan,
Freudenreich Catherine
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.542.11
Subject(s) - trinucleotide repeat expansion , homologous recombination , biology , dna repair , genetics , nuclear pore , genome instability , dna , dna ligase , nuclear protein , microbiology and biotechnology , dna damage , nucleus , gene , transcription factor , allele
Trinucleotide repeat expansions, such as CAG repeat expansions, cause more than 40 neurological disorders. CAG repeats are prone to break, and repair of the breaks can cause expansions. In yeast, some persistent DNA breaks are localized to the nuclear periphery which influences the break repair. We integrated an expanded CAG repeat into a yeast artificial chromosome (YAC) to evaluate the CAG repeat fragility and instability (contraction and expansion) in various nuclear periphery mutation backgrounds, as well as used fluorescent microscopy to study the localization of a GFP (green fluorescent protein)‐tagged CAG repeat in the nucleus over the cell cycle. Our results show that the Nup84 nuclear pore complex and its associated SUMO targeting ubiquitin ligase (STUbL), Slx5/Slx8, are crucial to maintain CAG repeat stability and prevent fragility. The repeat instability caused by deletion of Nup84 is dependent on the homologous recombination (HR) DNA break repair. Moreover, we found that expanded CAG‐70 and ‐130 repeats are more likely than a control to localize to the nuclear periphery during S‐phase. In conclusion, our study indicates that expanded CAG repeats localize to the nuclear periphery during S‐phase to promote proper repair in the presence of Nup84, which stabilizes CAG repeats by preventing aberrant HR repair. This study is funded by Tufts Department of Biology.