期刊
AGING-US
卷 13, 期 7, 页码 10490-10516出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.202810
关键词
alternative lengthening of telomeres; telomere-telomere recombination; nuclear envelope tethering; SUN1; RAP1
资金
- Center of Precision Medicine from The Featured Areas Research Center Program by the Ministry of Education (MOE)
- National Health Research Institutes (NHRI) [NHRIEX108-10825BI]
Telomere-nuclear envelope association may inhibit telomere-telomere recombination, with SUN1 depletion stimulating the formation of alternative lengthening of telomeres-associated promyelocytic leukemia bodies in ALT cells, while overexpression of the RAP1-SUN1 chimera protein suppresses APB formation.
Telomere length homeostasis is essential for maintaining genomic stability and cancer proliferation. Telomerase-negative cancer cells undergo recombination-mediated alternative lengthening of telomeres. Telomeres associate with the nuclear envelope through the shelterin RAP1 and nuclear envelope SUN1 proteins. However, how the associations between telomeres and the nuclear envelope affect the progression of telomere recombination is not understood. Here, we show that telomere anchorage might inhibit telomere-telomere recombination. SUN1 depletion stimulates the formation of alternative lengthening of telomeres-associated promyelocytic leukemia bodies in ALT cells. In contrast, overexpression of a telomere-nuclear envelope-tethering chimera protein, RAP1-SUN1, suppresses APB formation. Moreover, inhibition of this nuclear envelope attachment alleviates the requirement of TOP3 alpha for resolving the supercoiling pressure during telomere recombination. A coimmunoprecipitation assay revealed that the SUN1 N-terminal nucleoplasmic domain interacts with the RAP1 middle coil domain, and phosphorylation-mimetic mutations in RAP1 inhibit this interaction. However, abolishing the RAP1-SUN1 interaction does not hinder APB formation, which hints at the existence of another SUN1-dependent telomere anchorage pathway. In summary, our results reveal an inhibitory role of telomere-nuclear envelope association in telomere-telomere recombination and imply the presence of redundant pathways for the telomere-nuclear envelope association in ALT cells.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据