The structure of human CST reveals a decameric assembly bound to telomeric DNA

Lim, Ci Ji; Barbour, Alexandra T; Zaug, Arthur J.; Goodrich, Karen J.; McKay, Allison E.; Wuttke, Deborah S.; Cech, Thomas R.

doi:10.1126/science.aaz9649

Cited by 88 publications

(156 citation statements)

References 63 publications

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“…CST was identified as an RPA‐like protein complex due to its ssDNA‐binding ability and structural similarity to RPA (Miyake et al ., 2009; Lim et al ., 2020). Despite this similarity, recent discoveries on CST at stalled forks and DSBs suggest that CST is functionally distinct from RPA.…”

Section: Discussionmentioning

confidence: 99%

“…While our present data do not exclude the possible involvement of fill‐in synthesis in countering fork degradation, our results uncover a new function of CST in protecting fork stability and offer an alternative model that CST binds to ssDNA at reversed forks and directly inhibits MRE11 nuclease degradation, thereby protecting fork stability in a POLα‐independent manner (Fig 7D). Interestingly, while this manuscript was under review, the cryo‐EM structure of CST was reported, revealing that CST proteins are able to assemble into a decameric super complex when binding a 18‐nt ss telomeric oligo (Lim et al ., 2020). We speculate that if such or a similar structure can be formed at reversed forks, CST occupying 5’ overhangs may establish a physical barrier for MRE11 access to the 3’ end.…”

Section: Discussionmentioning

confidence: 99%

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Human CST complex protects stalled replication forks by directly blocking MRE11 degradation of nascent‐strand DNA

et al. 2020

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Degradation and collapse of stalled replication forks are main sources of genomic instability, yet the molecular mechanisms for protecting forks from degradation/collapse are not well understood. Here, we report that human CST (CTC1‐STN1‐TEN1) proteins, which form a single‐stranded DNA‐binding complex, localize at stalled forks and protect stalled forks from degradation by the MRE11 nuclease. CST deficiency increases MRE11 binding to stalled forks, leading to nascent‐strand degradation at reversed forks and ssDNA accumulation. In addition, purified CST complex binds to 5’ DNA overhangs and directly blocks MRE11 degradation in vitro, and the DNA‐binding ability of CST is required for blocking MRE11‐mediated nascent‐strand degradation. Our results suggest that CST inhibits MRE11 binding to reversed forks, thus antagonizing excessive nascent‐strand degradation. Finally, we uncover that CST complex inactivation exacerbates genome instability in BRCA2 deficient cells. Collectively, our findings identify the CST complex as an important fork protector that preserves genome integrity under replication perturbation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human CST complex protects stalled replication forks by directly blocking MRE11 degradation of nascent‐strand DNA

et al. 2020

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“…In budding yeast it is known as Cdc13-Stn1-Ten1 complex, however fission yeast lacks the CTC1/Cdc13 homolog, but contains Stn1 and Ten1 ( Martin et al, 2007 ). Recent cryo-EM structure of human CST reveals that it is capable of forming a decameric supercomplex when bound to telomeric ssDNA ( Lim et al, 2020 ). CTC1 is the largest subunit with a molecular weight of 134 kDa, and it possesses seven OB-fold domains ( Lim et al, 2020 ).…”

Section: Cstmentioning

confidence: 99%

“…Recent cryo-EM structure of human CST reveals that it is capable of forming a decameric supercomplex when bound to telomeric ssDNA ( Lim et al, 2020 ). CTC1 is the largest subunit with a molecular weight of 134 kDa, and it possesses seven OB-fold domains ( Lim et al, 2020 ). STN1 is 44 kDa and TEN1 is 13.8 kDa with one OB-fold each ( Figure 1A ; Rice and Skordalakes, 2016 ).…”

Section: Cstmentioning

confidence: 99%

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Roles of OB-Fold Proteins in Replication Stress

Nguyen

Kim

Sang

et al. 2020

Front. Cell Dev. Biol.

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Accurate DNA replication is essential for maintaining genome stability. However, this stability becomes vulnerable when replication fork progression is stalled or slowed – a condition known as replication stress. Prolonged fork stalling can cause DNA damage, leading to genome instabilities. Thus, cells have developed several pathways and a complex set of proteins to overcome the challenge at stalled replication forks. Oligonucleotide/oligosaccharide binding (OB)-fold containing proteins are a group of proteins that play a crucial role in fork protection and fork restart. These proteins bind to single-stranded DNA with high affinity and prevent premature annealing and unwanted nuclease digestion. Among these OB-fold containing proteins, the best studied in eukaryotic cells are replication protein A (RPA) and breast cancer susceptibility protein 2 (BRCA2). Recently, another RPA-like protein complex CTC1-STN1-TEN1 (CST) complex has been found to counter replication perturbation. In this review, we discuss the latest findings on how these OB-fold containing proteins (RPA, BRCA2, CST) cooperate to safeguard DNA replication and maintain genome stability.

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Occurrence, functionality and abundance of the TERT promoter mutations

Rachakonda

Hoheisel

Kumar

2021

Intl Journal of Cancer

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Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through the reactivation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene represent a definite mechanism for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate increase in TERT transcription and consequent telomerase upregulation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies have resolved the discrete aspects, effects and clinical relevance of the TERT promoter mutations. The promoter mutations link transcription of TERT with oncogenic pathways, associate with markers of poor outcome and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences, as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements. Besides, the evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

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The structure of human CST reveals a decameric assembly bound to telomeric DNA

Cited by 88 publications

References 63 publications

Human CST complex protects stalled replication forks by directly blocking MRE11 degradation of nascent‐strand DNA

Human CST complex protects stalled replication forks by directly blocking MRE11 degradation of nascent‐strand DNA

Roles of OB-Fold Proteins in Replication Stress

Occurrence, functionality and abundance of the TERT promoter mutations

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