Alternative paths to telomere elongation

Lee, Jennifer J.; Lee, Junyeop; Lee, Hyun‐Sook

doi:10.1016/j.semcdb.2020.11.003

Cited by 16 publications

(13 citation statements)

References 137 publications

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“…Recently, we showed that Brca2 deficiency results in induction of alternative lengthening of telomeres (ALT) through the instigation of the break-induced replication (BIR) 66 , 72 . According to the current study, the absence of BRCA2 will increase the level of G4 at telomeres.…”

Section: Discussionmentioning

confidence: 99%

Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis

et al. 2022

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BRCA2-deficient cells precipitate telomere shortening upon collapse of stalled replication forks. Here, we report that the dynamic interaction between BRCA2 and telomeric G-quadruplex (G4), the non-canonical four-stranded secondary structure, underlies telomere replication homeostasis. We find that the OB-folds of BRCA2 binds to telomeric G4, which can be an obstacle during replication. We further demonstrate that BRCA2 associates with G-triplex (G3)-derived intermediates, which are likely to form during direct interconversion between parallel and non-parallel G4. Intriguingly, BRCA2 binding to G3 intermediates promoted RAD51 recruitment to the telomere G4. Furthermore, MRE11 resected G4-telomere, which was inhibited by BRCA2. Pathogenic mutations at the OB-folds abrogated the binding with telomere G4, indicating that the way BRCA2 associates with telomere is innate to its tumor suppressor activity. Collectively, we propose that BRCA2 binding to telomeric G4 remodels it and allows RAD51-mediated restart of the G4-driven replication fork stalling, simultaneously preventing MRE11-mediated breakdown of telomere.

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Section: Discussionmentioning

confidence: 99%

Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis

et al. 2022

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“…This unique phenotype was positively associated with the retinal pathologies glaucoma and diabetic retinopathy. The authors suggested that the changes they observed were similar to alterations occurring in some central nervous cancer in which telomere length is maintained by a non-telomerase mechanism, alternative lengthening of telomeres (ALT), which is a kind of homology-directed DNA repair [53]. They concluded that the changes in telomere length they observed were associated with aging and retinal pathologies.…”

Section: Telomeres and Telomerase In Amdmentioning

confidence: 76%

Potential of Telomerase in Age-Related Macular Degeneration—Involvement of Senescence, DNA Damage Response and Autophagy and a Key Role of PGC-1α

Błasiak

Szczepańska

Fila

et al. 2021

IJMS

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Age-related macular degeneration (AMD), the main cause of vision loss in the elderly, is associated with oxidation in the retina cells promoting telomere attrition. Activation of telomerase was reported to improve macular functions in AMD patients. The catalytic subunit of human telomerase (hTERT) may directly interact with proteins important for senescence, DNA damage response, and autophagy, which are impaired in AMD. hTERT interaction with mTORC1 (mTOR (mechanistic target of rapamycin) complex 1) and PINK1 (PTEN-induced kinase 1) activates macroautophagy and mitophagy, respectively, and removes cellular debris accumulated over AMD progression. Ectopic expression of telomerase in retinal pigment epithelium (RPE) cells lengthened telomeres, reduced senescence, and extended their lifespan. These effects provide evidence for the potential of telomerase in AMD therapy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may be involved in AMD pathogenesis through decreasing oxidative stress and senescence, regulation of vascular endothelial growth factor (VEGF), and improving autophagy. PGC-1α and TERT form an inhibitory positive feedback loop. In conclusion, telomerase activation and its ectopic expression in RPE cells, as well as controlled clinical trials on the effects of telomerase activation in AMD patients, are justified and should be assisted by PGC-1α modulators to increase the therapeutic potential of telomerase in AMD.

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“…Recently, we showed that Brca2 deficiency results in induction of alternative lengthening of telomeres (ALT) through the instigation of the break-induced replication (BIR) 82,86 .…”

Section: Discussionmentioning

confidence: 99%

Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis

Lee¹,

Sung²,

Joo³

et al. 2021

Preprint

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BRCA2-deficient cells undergo telomere shortening upon collapse of stalled replication forks, particularly during lagging-strand telomere synthesis. The molecular mechanism underlying fork collapse remains unclear. Here we find that the BRCA2 C-terminus, which includes an OB-fold, specifically interacts with G-quadruplex (G4) structures generated during lagging-strand telomere replication. We demonstrate that BRCA2 associates with G-triplex (G3)-derived intermediates using electrophoretic mobility shift assay and single-molecule FRET. These G3 intermediates form during direct interconversion between parallel and non-parallel G4 structures. Intriguingly, MRE11 nuclease can resect G4-forming telomere sequences, a function that is inhibited by BRCA2. BRCA2 depletion consistently resulted in increased telomeric damage, which was relieved by MRE11 knockdown. These data suggest that BRCA2 interaction with telomeric G4 prevents MRE11-mediated resection. The specific interaction between BRCA2 and G4 therefore contributes to telomere stability and genome integrity.

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Alternative paths to telomere elongation

Cited by 16 publications

References 137 publications

Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis

Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis

Potential of Telomerase in Age-Related Macular Degeneration—Involvement of Senescence, DNA Damage Response and Autophagy and a Key Role of PGC-1α

Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis

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