期刊
NUCLEIC ACIDS RESEARCH
卷 49, 期 17, 页码 9886-9905出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab761
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资金
- Ligue Nationale Contre le Cancer (Ile de France committee)
- Association for Research against Cancer (Fondation ARC)
- AT Europe Association
- 'Radiobiology program' CEA grant
- INCA grant
- AFM grant
- INSERM
- french Ministry of Higher Education Research and Innovation (MESRI) from the ED of Cancerology (Gustave Roussy-University Paris-Saclay)
- Ligue Nationale Contre le Cancer fellowship (Haut-de-Seine committee)
- ERASMUS-Leonardo da Vinci program (Sapienza University, Roma)
- ED SDSV (University Paris-Saclay)
- Ligue Nationale Contre le Cancer
- Commissariat a l'Energie Atomique et aux Energies Alternatives
Overexpression of lamin B1 disrupts the shelterin complex, leading to telomere instability and aberrations in human cells. This dysregulation is associated with mislocalization of TRF2, and the interaction between lamin B1 and TRF2 at the nuclear periphery may play a role in telomere stability.
Telomere maintenance is essential to preserve genomic stability and involves telomere-specific proteins, DNA replication and repair proteins. Lamins are key components of the nuclear envelope and play numerous roles, including maintenance of the nuclear integrity, regulation of transcription, and DNA replication. Elevated levels of lamin B1, one of the major lamins, have been observed in some human pathologies and several cancers. Yet, the effect of lamin B1 dysregulation on telomere maintenance remains unknown. Here, we unveil that lamin B1 overexpression drives telomere instability through the disruption of the shelterin complex. Indeed, lamin B1 dysregulation leads to an increase in telomere dysfunction-induced foci, telomeric fusions and telomere losses in human cells. Telomere aberrations were preceded by mislocalizations of TRF2 and its binding partner RAP1. Interestingly, we identified new interactions between lamin B1 and these shelterin proteins, which are strongly enhanced at the nuclear periphery upon lamin B1 overexpression. Importantly, chromosomal fusions induced by lamin B1 in excess were rescued by TRF2 overexpression. These data indicated that lamin B1 overexpression triggers telomere instability through a mislocalization of TRF2. Altogether our results point to lamin B1 as a new interacting partner of TRF2, that is involved in telomere stability.
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