Human CTC1 promotes TopBP1 stability and CHK1 phosphorylation in response to telomere dysfunction and global replication stress

Sister chromatid cohesion (SCC), the pairing of sister chromatids after DNA replication until mitosis, is established by loading of the cohesin complex on newly replicated chromatids. Cohesin must then be maintained until mitosis to prevent segregation defects and aneuploidy. However, how SCC is established and maintained until mitosis remains incompletely understood, and emerging evidence suggests that replication stress may lead to premature SCC loss. Here, we report that the ssDNA-binding protein CTC1-STN1-TEN1 (CST) aids in SCC. CST primarily functions in telomere length regulation but also has known roles in replication restart and DNA repair. After depletion of CST subunits, we observed an increase in the complete loss of SCC. In addition, we determined that CST associates with the cohesin complex. Unexpectedly, we did not find evidence of altered cohesin loading or mitotic progression in the absence of CST; however, we did find that treatment with various replication inhibitors increased the association between CST and cohesin. Because replication stress was recently shown to induce SCC loss, we hypothesized that CST may be required to maintain or remodel SCC after DNA replication fork stalling. In agreement with this idea, SCC loss was greatly increased in CST-depleted cells after exogenous replication stress. Based on our findings, we propose that CST aids in the maintenance of SCC at stalled replication forks to prevent premature cohesion loss.

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“…This is likely due to HCT116 cells having an intact p53 response ( Fig. S1 G ) ( 22 ). In addition, CTC1 deletion ( 22 ) or STN1 depletion ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…S1 G ) ( 22 ). In addition, CTC1 deletion ( 22 ) or STN1 depletion ( Fig. S1 H ) in the HCT116 cells increased the number of G2/M, subG1, and aneuploid (>4n) cells, whereas no cell cycle defects were observed in HeLa ( 16 ) or HEK293T ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The DNA-binding protein CST associates with the cohesin complex and promotes chromosome cohesion

Schuck

Ball²,

Stewart³

2021

Journal of Biological Chemistry

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“…Under such conditions, 53BP1 may continue to block HR, while TRF2 is used to block NHEJ (Figure 9). In addition, deletion of CTC1 decreases TopBP1 and CHK1 phosphorylation, despite RPA-binding and ATR activation at telomeres (Ackerson et al, 2020). The loss of CHK1 signaling and 53BP1 localization could be sufficient to block the RPA-to-RAD51 exchange and, thus, HR-mediated FIGURE 9 | Potential mechanism for the protection of RPA-bound telomeres.…”

Section: Telomeresmentioning

confidence: 99%

To Join or Not to Join: Decision Points Along the Pathway to Double-Strand Break Repair vs. Chromosome End Protection

Ackerson

Romney

Schuck

et al. 2021

Front. Cell Dev. Biol.

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The regulation of DNA double-strand breaks (DSBs) and telomeres are diametrically opposed in the cell. DSBs are considered one of the most deleterious forms of DNA damage and must be quickly recognized and repaired. Telomeres, on the other hand, are specialized, stable DNA ends that must be protected from recognition as DSBs to inhibit unwanted chromosome fusions. Decisions to join DNA ends, or not, are therefore critical to genome stability. Yet, the processing of telomeres and DSBs share many commonalities. Accordingly, key decision points are used to shift DNA ends toward DSB repair vs. end protection. Additionally, DSBs can be repaired by two major pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ). The choice of which repair pathway is employed is also dictated by a series of decision points that shift the break toward HR or NHEJ. In this review, we will focus on these decision points and the mechanisms that dictate end protection vs. DSB repair and DSB repair choice.

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“…In S. cerevisiae, CST functions in chromosome end protection as well as regulating telomere length. In vertebrates, the shelterin complex is primarily responsible for end protection, but recent work suggests that CST may also function in end protection and the DDR at telomeres [45,46]. Generally, CST is involved in telomere length regulation where it terminates telomerase activity to prevent over-extension of the G-rich ssDNA overhang (G-overhang) and stimulates pol α activity to convert the overhang, generated by telomerase, back to duplex DNA, a process known as C-strand fill-in.…”

Section: Cstmentioning

confidence: 99%

“…Loss of CTC1 leads to telomere DNA damage signaling due to hyper-extension of G-overhangs and RPA binding [74]. Furthermore, treatment of CTC1 deleted cells with the ATR inhibitor VE-821 significantly increased apoptosis [46]. Therefore, targeting the OB-folds in CST to induce telomere dysfunction/genome instability along with DDR inhibitors may be an effective cancer therapy.…”

Section: Cstmentioning

confidence: 99%

OB-Folds and Genome Maintenance: Targeting Protein–DNA Interactions for Cancer Therapy

Par

Vaides

VanderVere-Carozza

et al. 2021

Cancers

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Genome stability and maintenance pathways along with their requisite proteins are critical for the accurate duplication of genetic material, mutation avoidance, and suppression of human diseases including cancer. Many of these proteins participate in these pathways by binding directly to DNA, and a subset employ oligonucleotide/oligosaccharide binding folds (OB-fold) to facilitate the protein–DNA interactions. OB-fold motifs allow for sequence independent binding to single-stranded DNA (ssDNA) and can serve to position specific proteins at specific DNA structures and then, via protein–protein interaction motifs, assemble the machinery to catalyze the replication, repair, or recombination of DNA. This review provides an overview of the OB-fold structural organization of some of the most relevant OB-fold containing proteins for oncology and drug discovery. We discuss their individual roles in DNA metabolism, progress toward drugging these motifs and their utility as potential cancer therapeutics. While protein–DNA interactions were initially thought to be undruggable, recent reports of success with molecules targeting OB-fold containing proteins suggest otherwise. The potential for the development of agents targeting OB-folds is in its infancy, but if successful, would expand the opportunities to impinge on genome stability and maintenance pathways for more effective cancer treatment.

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Human CTC1 promotes TopBP1 stability and CHK1 phosphorylation in response to telomere dysfunction and global replication stress

Cited by 14 publications

References 65 publications

The DNA-binding protein CST associates with the cohesin complex and promotes chromosome cohesion

The DNA-binding protein CST associates with the cohesin complex and promotes chromosome cohesion

To Join or Not to Join: Decision Points Along the Pathway to Double-Strand Break Repair vs. Chromosome End Protection

OB-Folds and Genome Maintenance: Targeting Protein–DNA Interactions for Cancer Therapy

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