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Defining the roles of ATR activators ETAA1 and TopB1 in the alternative lengthening of telomeres pathwayLock, Ying Jie 03 February 2022 (has links)
Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism utilized by a subset of cancers to promote replicative immortality. The ALT mechanism is driven by increased replication stress and persistent DNA damage response signaling that leads to a homology-directed repair mechanism called break-induced telomere synthesis (BITS). In particular, ALT cells are hypersensitive to inhibition of ataxia telangiectasia Rad3-related (ATR), a DNA damage response kinase implicated in telomere mobility and recruitment of repair proteins for telomere elongation in ALT. However, little is known about what regulates ATR activity at ALT telomeres. Given the importance of ATR in the ALT mechanism, we hypothesized that known ATR activators, ETAA1 and TopBP1, regulate ALT activity and telomere synthesis. Here, we show that ETAA1 and TopBP1 localize to ALT telomeres at sites of ALT activity and telomeric damage. Furthermore, depletion of ETAA1 and TopBP1 leads to defects in ATR signaling, a decrease in BITS and compensatory engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) for replication stress resolution. Taken together, our findings show that both ETAA1 and TopBP1 are important for mediating BITS at ALT telomeres and may better inform our efforts in targeting the ATR signaling pathway in ALT-positive cancers.
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Clarifying the Role of the CST Complex in DNA Replication and RepairWysong, Brandon Carter 12 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / 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 via 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 in vitro. 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.
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Clarifying the Role of the CST Complex in DNA Replication and RepairBrandon Carter Wysong (11519407) 20 December 2021 (has links)
<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>
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