Human PC4 supports telomere stability and viability in cells utilizing the alternative lengthening of telomeres mechanism.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2024-10-28 DOI:10.1038/s44319-024-00295-3

Sara Salgado, Patricia L Abreu, Beatriz Moleirinho, Daniela S Guedes, Lee Larcombe, Claus M Azzalin

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引用次数: 0

Abstract

Cancer cells with an activated Alternative Lengthening of Telomeres (ALT) mechanism elongate telomeres via homology-directed repair. Sustained telomeric replication stress is an essential trigger of ALT activity; however, it can lead to cell death if not properly restricted. By analyzing publicly available data from genome-wide CRISPR KO screenings, we have identified the multifunctional protein PC4 as a novel factor essential for ALT cell viability. Depletion of PC4 results in rapid ALT cell death, while telomerase-positive cells show minimal effects. PC4 depletion induces replication stress and telomere fragility primarily in ALT cells, and increases ALT activity. PC4 binds to telomeric DNA in cells, and its binding can be enhanced by telomeric replication stress. Finally, a mutant PC4 with partly impaired single stranded DNA binding activity is capable to localize to telomeres and suppress ALT activity and telomeric replication stress. We propose that PC4 supports ALT cell viability, at least partly, by averting telomere dysfunction. Further studies of PC4 interactions at ALT telomeres may hold promise for innovative therapies to eradicate ALT cancers.

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人类 PC4 利用端粒替代性延长机制支持端粒稳定性和细胞活力。

激活了端粒替代性延长（ALT）机制的癌细胞会通过同源定向修复来延长端粒。持续的端粒复制压力是 ALT 活性的重要触发因素；但是，如果不加以适当限制，它可能会导致细胞死亡。通过分析从全基因组 CRISPR KO 筛选中公开获得的数据，我们发现多功能蛋白 PC4 是 ALT 细胞存活所必需的新型因子。消耗 PC4 会导致 ALT 细胞快速死亡，而端粒酶阳性细胞受到的影响最小。PC4 的耗竭主要会诱导 ALT 细胞的复制压力和端粒脆性，并增加 ALT 的活性。PC4 可与细胞中的端粒 DNA 结合，端粒复制压力可增强其结合力。最后，单链DNA结合活性部分受损的突变体PC4能够定位到端粒并抑制ALT活性和端粒复制压力。我们认为，PC4 至少部分地通过避免端粒功能障碍来支持 ALT 细胞的活力。进一步研究PC4在ALT端粒上的相互作用可能会为根除ALT癌症的创新疗法带来希望。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.