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A Novel Role of the Human CST Complex in Regulating the DNA Damage Response
Author(s) -
Stewart Jason A.,
Ackerson Stephanie M.
Publication year - 2018
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.2018.32.1_supplement.522.9
Subject(s) - genome instability , dna damage , microbiology and biotechnology , dna replication , biology , telomere , origin recognition complex , dna repair , dna , dna re replication , pre replication complex , replication protein a , eukaryotic dna replication , genetics , dna binding protein , gene , transcription factor
CST (CTC1‐STN1‐TEN1) is an RPA‐like, ssDNA binding protein that functions in telomere replication and genome‐wide DNA replication rescue. Previous studies have shown that depletion of STN1 or CST overexpression leads to decreased or increased new origin firing following replication stress, suggesting a role for CST in dormant origin activation. Additionally, depletion of CST subunits leads to increased anaphase bridges and micronuclei. Recently, a conditional CTC1 knockout line was created in HCT116 cells. Removal of CTC1 was found to cause decreased cell proliferation and elongation of the telomeric ssDNA G‐overhang, leading to RPA accumulation and telomeric DNA damage signaling. Interestingly, rescue of the telomeric damage did not restore normal cell growth, suggesting that other factors contribute to the growth defects in the absence of CTC1. Here, we investigate the consequences of CTC1 deletion on genome‐wide replication and activation of the DNA damage response. We find that CTC1 deletion lead to a delayed but abrupt activation of p53 and p21 leading to decreased DNA replication and a G2/M arrest. We hypothesized that this cell cycle arrest was caused by ATR activation from defects in telomere or genome‐wide DNA replication. Instead, our results suggest that ATR signaling is defective in the absence of CTC1 and p53 is activated in an ATR‐independent manner. Overall, our findings suggest a novel and unexpected role of CST in promoting checkpoint signaling to prevent genome instability. Support or Funding Information This work is supported by the National Institutes of Health grant R00 GM104409 and startup funds from the University of South Carolina. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .