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서울대학교

Nucleic Acids Res., Apr 08 2024, gkae251 | https://doi.org/10.1093/nar/gkae251 Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres

Jennifer J. Lee¹, Hyungmin Kim¹, Haemin Park¹, UkJin Lee¹, Chaelim Kim², Min Lee², Yongdae Shin^2,3, Ji-Jung Jung⁴, Han-Byoel Lee^4,5,6, Wonshik Han^4,5,6 and Hyunsook Lee^1,*

¹Department of Biological Sciences & Institute of Molecular Biology and Genetics (IMBG), Seoul National University, 1 Gwanak-Ro, Gwanak-Gu, Seoul 08826, Korea

²Interdisciplinary Program in Bioengineering, Seoul National University, Seoul 08826, Korea

³Department of Mechanical Engineering, Seoul National University, Seoul 08826, Korea

⁴Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea

⁵Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea

⁶Cancer Research Institute, Seoul National University, Seoul 03080, Korea

^*To whom correspondence should be addressed: Hyunsook Lee

Abstract

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.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-09)
연구진국내 연구진
분야 생명과학 > 세포생물학

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