Deficiency in mammalian STN1 promotes colon cancer development via inhibiting DNA repair

Nguyễn, Văn Khánh; Kim, Eugene; Le, Ngoan Tran; Ding, Xianzhong; Jaiswal, Rishi Kumar; Kostlan, Raymond J.; Nguyen, Thi Ngoc Thanh; Shiva, Olga; Lee, Wang Jae; Chai, Weihang

doi:10.1126/sciadv.add8023

Cited by 8 publications

(3 citation statements)

References 113 publications

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“…Consequently, this process leads to the creation of DNA single-stranded breaks (SSBs), which are then converted to double-strand breaks during DNA replication ( 45 ). The neutral comet assay detected this DNA damage as the ‘comet’ tail shape and migration, representing the extent of the DNA damage (Figure 6B , C ) ( 22 ). Elevated levels of γH2AX expression indicated the occurrence of double-strand breaks in cells (Figure 6D , E ).…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, in AAG (human alkyl adenine DNA glycosylase)-mediated neutral electrophoresis, the protocol previously outlined by Nguyen et al. ( 22 ) was followed. After cell lysis, the cells were treated with TMZ (100 μM, except for the control sample) at 37°C for 6 h. This was followed by an enzymatic reaction with 10 U of hAAU in 1× NEB ThermoPol reaction buffer ( Supplementary Table S2 ) at 37°C for 1 h. Subsequently, RA-1 (5 μM) was added to the combination sample, which was incubated for 2 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

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DNA abasic sites act as rational therapeutic targets to synergize temozolomide response in both MMR-proficient and deficient cancer

Bora,

Pal,

Mandi

et al. 2024

NAR Cancer

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Temozolomide (TMZ) is widely used in cancer treatment, yet resistance to this agent limits its therapeutic effectiveness, particularly in mismatch-repair (MMR) deficient cancer. Concurrently, the Base Excision Repair (BER) pathway exerts a mitigating role. Our results demonstrated that the increasing TMZ concentrations correlate with an elevated accumulation of DNA abasic sites via the BER pathway in both MMR-proficient and deficient cancer cells, implicating abasic sites as promising targets to enhance the TMZ response. Amino-quinoxaline small molecules (RA-1) have been developed, whose hydrophobic core facilitates selective binding to apurinic/apyrimidinic (AP) sites, particularly adenine as the complementary nucleobase opposite to the AP-sites via base stacking. RA-1 effectively cleaves TMZ-induced DNA abasic sites in-vitro at minimal concentrations through Schiff-base formation. Remarkably, the combination of TMZ and RA-1 exerts a notable synergistic effect on both types of cells. The underlying mechanism of this synergy is rooted in the cleavage of TMZ-induced DNA abasic sites, which impairs the BER pathway, leading to the formation of DNA double-strand breaks. Consequently, the ATM-Chk2/ATR-Chk1 signalling pathways are activated, prompting S-phase arrest and ultimately driving apoptosis. These findings provide a compelling rationale for targeting DNA abasic sites to synergistically augment TMZ responses in both MMR-proficient and deficient cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

DNA abasic sites act as rational therapeutic targets to synergize temozolomide response in both MMR-proficient and deficient cancer

Bora,

Pal,

Mandi

et al. 2024

NAR Cancer

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“…We have not addressed the question of whether the CST complex plays a role in SSB repair or not, which should be investigated in a future separate study. It is of note, however, that while our manuscript was in preparation, STN1 deficiency was reported to down-regulate DNA glycosylases and thus suppress base excision repair (BER), leading to an increased oxidative DNA damage and risk of colon cancer [ 51 ]. Therefore, the CST complex might regulate different DNA repair mechanisms depending on the sources and doses of the oxidative stress and possibly cell types.…”

Section: Discussionmentioning

confidence: 99%

The CST complex facilitates cell survival under oxidative genotoxic stress

Hara,

Nakaoka,

Miyoshi

et al. 2023

PLoS ONE

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Genomic DNA is constantly exposed to a variety of genotoxic stresses, and it is crucial for organisms to be equipped with mechanisms for repairing the damaged genome. Previously, it was demonstrated that the mammalian CST (CTC1-STN1-TEN1) complex, which was originally identified as a single-stranded DNA-binding trimeric protein complex essential for telomere maintenance, is required for survival in response to hydroxyurea (HU), which induces DNA replication fork stalling. It is still unclear, however, how the CST complex is involved in the repair of diverse types of DNA damage induced by oxidizing agents such as H2O2. STN1 knockdown (KD) sensitized HeLa cells to high doses of H2O2. While H2O2 induced DNA strand breaks throughout the cell cycle, STN1 KD cells were as resistant as control cells to H2O2 treatment when challenged in the G1 phase of the cell cycle, but they were sensitive when exposed to H2O2 in S/G2/M phase. STN1 KD cells showed a failure of DNA synthesis and RAD51 foci formation upon H2O2 treatment. Chemical inhibition of RAD51 in shSTN1 cells did not exacerbate the sensitivity to H2O2, implying that the CST complex and RAD51 act in the same pathway. Collectively, our results suggest that the CST complex is required for maintaining genomic stability in response to oxidative DNA damage, possibly through RAD51-dependent DNA repair/protection mechanisms.

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Human CST Stimulates Base Excision Repair to Prevent the Accumulation of Oxidative DNA Damage

Wysong,

Schuck,

Sridharan

et al. 2024

Journal of Molecular Biology

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Deficiency in mammalian STN1 promotes colon cancer development via inhibiting DNA repair

Cited by 8 publications

References 113 publications

DNA abasic sites act as rational therapeutic targets to synergize temozolomide response in both MMR-proficient and deficient cancer

DNA abasic sites act as rational therapeutic targets to synergize temozolomide response in both MMR-proficient and deficient cancer

The CST complex facilitates cell survival under oxidative genotoxic stress

Human CST Stimulates Base Excision Repair to Prevent the Accumulation of Oxidative DNA Damage

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