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

Lee, Junyeop; Sung, Keewon; Joo, So Young; Jeong, Jun-Hyeon; Kim, Seong Keun; Lee, Hyun‐Sook

doi:10.1038/s41467-022-31156-z

Cited by 13 publications

(43 citation statements)

References 78 publications

(102 reference statements)

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“…Guanine quadruplexes (GQs) are a common non-canonical form of nucleic acids. They are formed by sequences rich in guanine (G), which are widespreadhundreds of thousands of known and putative sites have been identified in the human genome. , Notably, GQs are abundant in gene regulatory parts and in the telomeric region, where they play roles in maintaining cell function and genome integrity. − Mutations leading to over- or under-formation of G4s often lead to diseases, such as cancer − or neuropathologies. − …”

Section: Introductionmentioning

confidence: 99%

Complexity of Guanine Quadruplex Unfolding Pathways Revealed by Atomistic Pulling Simulations

Stadlbauer

Mlýnský

Krepl

et al. 2023

J. Chem. Inf. Model.

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Guanine quadruplexes (GQs) are non-canonical nucleic acid structures involved in many biological processes. GQs formed in single-stranded regions often need to be unwound by cellular machinery, so their mechanochemical properties are important. Here, we performed steered molecular dynamics simulations of human telomeric GQs to study their unfolding. We examined four pulling regimes, including a very slow setup with pulling velocity and force load accessible to high-speed atomic force microscopy. We identified multiple factors affecting the unfolding mechanism, i.e.,: (i) the more the direction of force was perpendicular to the GQ channel axis (determined by GQ topology), the more the base unzipping mechanism happened, (ii) the more parallel the direction of force was, GQ opening and cross-like GQs were more likely to occur, (iii) strand slippage mechanism was possible for GQs with an all-anti pattern in a strand, and (iv) slower pulling velocity led to richer structural dynamics with sampling of more intermediates and partial refolding events. We also identified that a GQ may eventually unfold after a force drop under forces smaller than those that the GQ withstood before the drop. Finally, we found out that different unfolding intermediates could have very similar chain end-to-end distances, which reveals some limitations of structural interpretations of single-molecule spectroscopic data.

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Section: Introductionmentioning

confidence: 99%

Complexity of Guanine Quadruplex Unfolding Pathways Revealed by Atomistic Pulling Simulations

Stadlbauer

Mlýnský

Krepl

et al. 2023

J. Chem. Inf. Model.

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“…Consistent with these findings, we showed that BRCA2 is required for the formation of C-circles, an important ALT biomarker, in ALT+ cells that experience severe replication stress at their telomeres ( Pan et al, 2019 ). Most intriguingly, Lee and colleagues demonstrated recently that BRCA2 directly binds the telomeric G4s in vitro , suggesting that it may be involved in disrupting the G4 accumulation, thereby preventing replication fork stalling at telomeres ( Lee et al, 2022 ).…”

Section: Molecular Mechanism Behind the Clinical Efficacy Of Parp Inh...mentioning

confidence: 99%

Targeting the BRCA1/2 deficient cancer with PARP inhibitors: Clinical outcomes and mechanistic insights

Ragupathi

Singh

Perez

et al. 2023

Front. Cell Dev. Biol.

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BRCA1 and BRCA2 play a critical role in a variety of molecular processes related to DNA metabolism, including homologous recombination and mediating the replication stress response. Individuals with mutations in the BRCA1 and BRCA2 (BRCA1/2) genes have a significantly higher risk of developing various types of cancers, especially cancers of the breast, ovary, pancreas, and prostate. Currently, the Food and Drug Administration (FDA) has approved four PARP inhibitors (PARPi) to treat cancers with BRCA1/2 mutations. In this review, we will first summarize the clinical outcomes of the four FDA-approved PARPi in treating BRCA1/2 deficient cancers. We will then discuss evidence supporting the hypothesis that the cytotoxic effect of PARPi is likely due to inducing excessive replication stress at the difficult-to-replicate (DTR) genomic regions in BRCA1/2 mutated tumors. Finally, we will discuss the ongoing preclinical and clinical studies on how to combine the PARPi with immuno-oncology drugs to further improve clinical outcomes.

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“…We recently reported that BRCA2 recognizes dynamically interconverting telomere G-quadruplex (G4), a G-rich four-stranded nucleic acid structure. Specifically, we demonstrated that BRCA2 directly binds to G-triplex (G3) intermediates during dynamic interconversion between parallel and non-parallel telomeric G4s ( 9 ). The binding of BRCA2 to G3 protects telomeric G4, which would otherwise be susceptible to attack by nuclease MRE11.…”

Section: Introductionmentioning

confidence: 99%

“…The binding of BRCA2 to G3 protects telomeric G4, which would otherwise be susceptible to attack by nuclease MRE11. At the same time, BRCA2 binding to G3 enables RAD51 loading to single-stranded regions in G3, facilitating the remodeling of the stalled replication fork and restarting telomere replication ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres

Lee,

Kim,

Park

et al. 2024

Nucleic Acids Research

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Dynamic interaction between BRCA2 and telomeric G-quadruplexes (G4) is crucial for maintaining telomere replication homeostasis. Cells lacking BRCA2 display telomeric damage with a subset of these cells bypassing senescence to initiate break-induced replication (BIR) for telomere synthesis. Here we show that the abnormal stabilization of telomeric G4 following BRCA2 depletion leads to telomeric repeat-containing RNA (TERRA)-R-loop accumulation, triggering liquid–liquid phase separation (LLPS) and the assembly of Alternative Lengthening of Telomeres (ALT)-associated promyelocytic leukemia (PML) bodies (APBs). Disruption of R-loops abolishes LLPS and impairs telomere synthesis. Artificial engineering of telomeric LLPS restores telomere synthesis, underscoring the critical role of LLPS in ALT. TERRA-R-loops also recruit Polycomb Repressive Complex 2 (PRC2), leading to tri-methylation of Lys27 on histone H3 (H3K27me3) at telomeres. Half of paraffin-embedded tissue sections from human breast cancers exhibit APBs and telomere length heterogeneity, suggesting that BRCA2 mutations can predispose individuals to ALT-type tumorigenesis. Overall, BRCA2 abrogation disrupts the dynamicity of telomeric G4, producing TERRA-R-loops, finally leading to the assembly of telomeric liquid condensates crucial for ALT. We propose that modulating the dynamicity of telomeric G4 and targeting TERRA-R-loops in telomeric LLPS maintenance may represent effective therapeutic strategies for treating ALT-like cancers with APBs, including those with BRCA2 disruptions.

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

Cited by 13 publications

References 78 publications

Complexity of Guanine Quadruplex Unfolding Pathways Revealed by Atomistic Pulling Simulations

Complexity of Guanine Quadruplex Unfolding Pathways Revealed by Atomistic Pulling Simulations

Targeting the BRCA1/2 deficient cancer with PARP inhibitors: Clinical outcomes and mechanistic insights

Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres

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