<p>Ends of linear chromosomes are maintained by specialized
structures known as telomeres. These
structures are protected by a number of essential protein complexes including
the shelterin complex and CST (CTC1 – STN1 – TEN1) complex. CST is an RPA-like ssDNA binding protein that
is vital for telomere length maintenance <i>via</i> inhibition of telomerase
and stimulation of DNA polymerase α -primase during C-strand fill-in synthesis.
CST is also known to possess additional genome-wide
roles in regulating DNA replication and repair including helping facilitate
replication re-start at stalled forks, activating checkpoint signaling at
double-strand breaks, and promoting replication origin firing. Proper and efficient repair of DNA is
critical in order to protect the integrity of the genome and prevent extreme
mutagenesis. Telomeres have a strong
predisposition to oxidative DNA damage in the form of 8-oxoguanine caused by
exposure to reactive oxygen species and free radicals. These oxidative lesions are repaired by the
base-excision repair (BER) pathway.
Previous work has implicated telomeric proteins such as the shelterin
complex in mediating BER. Here we show
for the first time that the CST complex and individual subunits robustly
stimulate a myriad of proteins involved in the BER pathway including Pol β,
APE1, FEN1, and LIGI. CST’s ability to
augment these BER-associated proteins could be instrumental in promoting
efficient DNA repair. Additionally, we
find that CTC1 and STN1 are able to significantly enhance the polymerase
activity of Pol δ and Pol α on both random-sequence and telomeric-sequence DNA
substrates <i>in vitro</i>. What is more, we establish the ability of CST
to resolve G4 structure and promote Pol δ synthesis, which we predict is a key
feature of CST’s involvement in DNA replication at telomeres, which are known
to form replication-inhibiting G4’s. Our
results define important mechanistic insight into CST’s role in DNA replication
and repair, and provide a strong foundation for future studies relating
defective telomere maintenance to aging disorders and cancers which impact
human health.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/16732801 |
| Date | 20 December 2021 |
| Creators | Brandon Carter Wysong (11519407) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/Clarifying_the_Role_of_the_CST_Complex_in_DNA_Replication_and_Repair/16732801 |
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