CST in maintaining genome stability: Beyond telomeres

Lyu, Xinxing; Sang, Pau Biak; Chai, Weihang

doi:10.1016/j.dnarep.2021.103104

Cited by 23 publications

(19 citation statements)

References 112 publications

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“…RTEL1 is required for the unwinding DNA at a replication fork. The CST complex (CTC1, STN1, TEN1) regulates telomerase activity and promotes the C-strand telomerase-independent telomere replication by primase and DNA polymerase alpha ( Lyu et al, 2021 ).…”

Section: Figmentioning

confidence: 99%

Stress and telomere shortening: Insights from cellular mechanisms

Lin¹,

Epel

2022

Ageing Research Reviews

182

124

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Section: Figmentioning

confidence: 99%

Stress and telomere shortening: Insights from cellular mechanisms

Lin¹,

Epel

2022

Ageing Research Reviews

182

124

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“…The human CST trimeric complex has emerged as an important constituent that ensures faithful replication of genomic DNA, especially when replication is perturbed. It localizes at stalled replication forks and protects nascent strand DNA from being degraded by unscheduled nuclease degradation [12]. In this study, we report that the OB-fold structure of STN1-TEN1 is strikingly similar to that of RPA32-RPA14 (Figure 1B).…”

Section: Discussionmentioning

confidence: 51%

“…While it is considered RPA-like, CST possesses functions distinct from RPA in fork protection and DSB repair. At stalled forks, CST binding to DNA prevents unscheduled MRE11 degradation of nascent strand DNA, while RPA has limited protection against MRE11 [12]. CST facilitates RAD51 recruitment to forks, whereas RPA-coated ssDNA inhibits RAD51 nuclear filament formation [18].…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies have shown that CST is an important player in maintaining genome stability and telomere integrity [12]. Its telomeric functions include promoting efficient replication of telomeric DNA, preventing the accumulation of ssDNA in telomeric DNA, assisting POLα in synthesizing C-rich strands and thereby replenishing C-strand DNA, and restricting telomerase from excessively elongating telomeres [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…Firstly, upon hydroxyurea (HU)-induced fork stalling, CST assists in RAD51 recruitment to stalled forks, whereas prior binding of RPA to ssDNA inhibits RAD51 filament formation [18,24,25]. Secondly, CST binding to DNA can directly block unscheduled MRE11 degradation of nascent strand DNA at reversed forks, while RPA binding to DNA has limited protection against MRE11 degradation [12]. At double-strand breaks (DSBs), CST interacts with the Shieldin complex and counters excessive end resection, thereby promoting canonical nonhomologous end-joining (c-NHEJ) [26,27].…”

Section: Introductionmentioning

confidence: 99%

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The Intrinsically Disordered Region in the Human STN1 OB-Fold Domain Is Important for Protecting Genome Stability

Chai

Chastain

Shiva

et al. 2021

Biology

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The mammalian CTC1–STN1–TEN1 (CST) complex is an ssDNA-binding protein complex that has emerged as an important player in protecting genome stability and preserving telomere integrity. Studies have shown that CST localizes at stalled replication forks and is critical for protecting the stability of nascent strand DNA. Recent cryo-EM analysis reveals that CST subunits possess multiple OB-fold domains that can form a decameric supercomplex. While considered to be RPA-like, CST acts distinctly from RPA to protect genome stability. Here, we report that while the OB domain of STN1 shares structural similarity with the OB domain of RPA32, the STN1-OB domain contains an intrinsically disordered region (IDR) that is important for maintaining genome stability under replication stress. Single mutations in multiple positions in this IDR, including cancer-associated mutations, cause genome instabilities that are elevated by replication stress and display reduced cellular viability and increased HU sensitivity. While IDR mutations do not impact CST complex formation or CST interaction with its binding partner RAD51, they diminish RAD51 foci formation when replication is perturbed. Interestingly, the IDR is critical for STN1–POLα interaction. Collectively, our results identify the STN1 IDR as an important element in regulating CST function in genome stability maintenance.

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