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The Role of The DNA Damage Checkpoint in The Relocalization of CAG Trinucleotide Repeats to The Nuclear Pore Complex During S‐phase
Author(s) -
Johnson Matthew,
Whalen Jenna,
Freudenreich Catherine
Publication year - 2020
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.2020.34.s1.09028
Subject(s) - g2 m dna damage checkpoint , dna damage , trinucleotide repeat expansion , biology , myotonic dystrophy , dna repair , dna replication , genetics , microbiology and biotechnology , dna , mutation , chek1 , gene , cell cycle checkpoint , cell cycle , allele
The instability of CAG trinucleotide repeats has been known to cause neurodegenerative diseases including Huntington’s disease and myotonic muscular dystrophy. Moreover, CAG trinucleotide repeats are capable of forming lesion inducing hairpin structures during the replication of DNA during S‐phase. These lesions must be repaired in order for DNA to be faithfully replicated and properly segregated during mitotic division. Failure to correct these lesions may result in deleterious mutations at these sequences. The DNA damage checkpoint elicits the first response to damage including double stranded breaks and collapsed replication forks resulting from CAG hairpin stalling. Notably, these collapsed forks are relocalized from the center of the nucleus to the nuclear pore complex (NPC) for repair. It is hypothesized that the DNA damage checkpoint plays a role in signaling relocalization of these lesions to the NPC during S‐phase. To test this hypothesis, a GFP based zoning assay system was designed to assess CAG repeat relocalization to the NPC in several gene backgrounds defective in the DNA damage checkpoint response. These zoning assays have indicated that the DNA damage checkpoint does indeed play a role in the relocalization of CAG repeats during S‐phase. Several mutants tested also displayed abnormal nuclear arrangement. This research demonstrates that the DNA damage checkpoint is necessary for the relocalization of CAG tracts to the NPC which is known to be necessary for repair of persistent DNA lesions. Further studies will determine the mechanisms by which the checkpoint is involved in this relocalization and why abnormal nuclear arrangement is sometimes seen in mutants that are unable to elicit a proper checkpoint response. Support or Funding Information All support and funding is provided through the Tufts University Biology Department and specifically the Freudenreich Lab.