NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres

Rai, Rekha; Hu, Chunyi; Broton, Cayla; Chen, Yong; Lei, Ming; Chang, Sandy

doi:10.1016/j.molcel.2017.01.016

Cited by 51 publications

(77 citation statements)

References 74 publications

(110 reference statements)

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“…NBS1 co-crystallizes with TRF2 (179). NBS1 phosphorylation at S432 residue inhibits this interaction and promotes C-NHEJ at telomeres lacking TRF2 (179).…”

Section: Mrn and Dysfunctional Telomeresmentioning

confidence: 99%

“…NBS1 co-crystallizes with TRF2 (179). NBS1 phosphorylation at S432 residue inhibits this interaction and promotes C-NHEJ at telomeres lacking TRF2 (179). Yet, NBS1 phosphorylation at the same site promotes A-NHEJ at telomeres lacking POT1–TPP1 (179).…”

Section: Mrn and Dysfunctional Telomeresmentioning

confidence: 99%

“…NBS1 phosphorylation at S432 residue inhibits this interaction and promotes C-NHEJ at telomeres lacking TRF2 (179). Yet, NBS1 phosphorylation at the same site promotes A-NHEJ at telomeres lacking POT1–TPP1 (179). In addition to defective shelterin components, critically short or deleted ends lead to dysfunctional telomeres.…”

Section: Mrn and Dysfunctional Telomeresmentioning

confidence: 99%

See 2 more Smart Citations

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

Syed

Tainer

2018

Annu. Rev. Biochem.

326

345

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Genomic instability in disease and its fidelity in health depend on the DNA damage response (DDR), regulated in part from the complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette–ATPase (RAD50), and phosphopeptide-binding Nijmegen breakage syndrome protein 1 (NBS1). The MRE11–RAD50–NBS1 (MRN) complex forms a multifunctional DDR machine. Within its network assemblies, MRN is the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection. MRN can interfere with cancer therapy and is an attractive target for precision medicine. Its conformations change the paradigm whereby kinases initiate damage sensing. Delineated results reveal kinase activation, posttranslational targeting, functional scaffolding, conformations storing binding energy and en-abling access, interactions with hub proteins such as replication protein A (RPA), and distinct networks at DNA breaks and forks. MRN biochemistry provides prototypic insights into how it initiates, implements, and regulates multifunctional responses to genomic stress.

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“…NBS1 co-crystallizes with TRF2 (179). NBS1 phosphorylation at S432 residue inhibits this interaction and promotes C-NHEJ at telomeres lacking TRF2 (179).…”

Section: Mrn and Dysfunctional Telomeresmentioning

confidence: 99%

Section: Mrn and Dysfunctional Telomeresmentioning

confidence: 99%

Section: Mrn and Dysfunctional Telomeresmentioning

confidence: 99%

See 1 more Smart Citation

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

Syed

Tainer

2018

Annu. Rev. Biochem.

326

345

View full text Add to dashboard Cite

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“…The TRF2-Apollo interaction is restricted to S/G2 phase, and occurs after leading-strand synthesis. This interaction is mediated by S/G2 phasespecific NBS1 phosphorylation by CDK, which dissociates NBS1 from TRF2 and enables TRF2 to recruit Apollo (Rai et al, 2017).…”

Section: The Response To Dysfunctional Telomeresmentioning

confidence: 99%

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

Muraki

Murnane

2017

Genes Genet. Syst.

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In mammals, DNA double-strand breaks (DSBs) are primarily repaired by classical non-homologous end joining (C-NHEJ), although homologous recombination repair and alternative NHEJ (A-NHEJ), which involve DSB processing, can also occur. These pathways are tightly regulated to maintain chromosome integrity. The ends of chromosomes, called telomeres, contain telomeric DNA that forms a cap structure in cooperation with telomeric proteins to prevent the activation of the DNA damage response and chromosome fusion at chromosome termini. Telomeres and subtelomeric regions are poor substrates for DNA replication; therefore, regions near telomeres are prone to replication fork stalling and chromosome breakage. Moreover, DSBs near telomeres are poorly repaired. As a result, when DSBs occur near telomeres in normal cells, the cells stop proliferating, while in cancer cells, subtelomeric DSBs induce rearrangements due to the absence of cell cycle checkpoints. The sensitivity of subtelomeric regions to DSBs is due to the improper regulation of processing, because although C-NHEJ is functional at subtelomeric DSBs, excessive processing results in an increased frequency of large deletions and chromosome rearrangements involving A-NHEJ.

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“…For example, removal of TRF2 activates ATM to promote classical nonhomologous end joining (C‐NHEJ)‐mediated repair, while removal of TPP1:POT1 activates ATR and telomere repair via alternative (A)‐NHEJ‐mediated repair. Finally, RAP1 and TRF2 coordinate to repress the activation of homology‐directed DNA repair (Denchi & de Lange, 2007; Guo et al., 2007; Rai, Chen, Lei & Chang, 2016; Rai et al., 2017). …”

Section: Introductionmentioning

confidence: 99%

CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length

Jia

Takasugi

et al. 2018

Aging Cell

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SummaryCoats plus (CP) is a rare autosomal recessive disorder caused by mutations in CTC1, a component of the CST (CTC1, STN1, and TEN1) complex important for telomere length maintenance. The molecular basis of how CP mutations impact upon telomere length remains unclear. The CP CTC1L1142H mutation has been previously shown to disrupt telomere maintenance. In this study, we used CRISPR/Cas9 to engineer this mutation into both alleles of HCT116 and RPE cells to demonstrate that CTC1:STN1 interaction is required to repress telomerase activity. CTC1L1142H interacts poorly with STN1, leading to telomerase‐mediated telomere elongation. Impaired interaction between CTC1L1142H:STN1 and DNA Pol‐α results in increased telomerase recruitment to telomeres and further telomere elongation, revealing that C:S binding to DNA Pol‐α is required to fully repress telomerase activity. CP CTC1 mutants that fail to interact with DNA Pol‐α resulted in loss of C‐strand maintenance and catastrophic telomere shortening. Our findings place the CST complex as an important regulator of both G‐strand extensions by telomerase and C‐strand synthesis by DNA Pol‐α.

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NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres

Cited by 51 publications

References 74 publications

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length

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