匹兹堡大学Roderick J. O’Sullivan课题组取得一项新突破。他们的最新研究探明了着丝粒足迹在ALT癌症中保持端粒完整性。这一研究成果于2026年6月3日发表在国际顶尖学术期刊《自然》上。
在这里，该课题组报道了在ALT癌细胞系和原发性ALT儿童神经母细胞瘤的端粒位置插入着丝粒α-卫星重复序列和CENP-B盒，表明这种改变存在病理联系。利用长读测序（DiMeLo-seq）对定向甲基化进行分析，揭示了在染色体亚群端粒位置组装的CENP-A染色质的离散足迹。通过模拟ALT激活，课题组人员发现由于ATRX缺失和DNA低甲基化导致的表观遗传失调促进了这些着丝粒染色质特征的获取。在功能上，干扰HJURP介导的CENP-A沉积会损害端粒完整性和ALT，导致端粒有丝分裂DNA合成异常（MiDAS）。该课题组人员提出，虽然最初是由非法重组产生的，但在ALT癌细胞的独特背景下，这些着丝粒特征通过维持端粒染色质的完整性而成为不可或缺的。
据悉，端粒选择性延长（ALT）是一种特殊的端粒延长机制，与5-10%的癌症有关。虽然ALT与表观遗传失调和基因组不稳定有关，但ALT激活后产生的特异性基因组和表观遗传重排尚未确定。
附：英文原文
Title: Centromeric footprints preserve telomere integrity in ALT cancers
Author: Bhargava, Ragini, Mahlke, Megan A., Schmidt, Tobias T., Bartenhagen, Christoph, Smith, Baylee A., Ramsey, Katherine L., Zuehlke, Takoda T., Bowman, Ray W., Lynskey, Michelle L., Wondisford, Anne R., Ouriou, Jean-Baptiste, Schamus-Hayes, Sandra, Calderon, Michael J., Watkins, Simon C., Williams-Wehner, April E., Bone, Jennifer M., Joglekar, Alok V., Fischer, Matthias, Karlseder, Jan, Nechemia-Arbely, Yael, OSullivan, Roderick J.
Issue&Volume: 2026-06-03
Abstract: Alternative lengthening of telomeres (ALT) is a specialized telomere extension mechanism associated with 5–10% of all cancers1. Although ALT has been linked to epigenetic dysregulation and genome instability, specific genomic and epigenetic rearrangements generated after ALT activation have not been identified. Here we report the insertion of centromeric α-satellite repeats and CENP-B boxes at telomeric locations specifically in ALT cancer cell lines and primary ALT paediatric neuroblastomas, indicating a pathological link for this alteration. Analysis using directed methylation with long-read sequencing (DiMeLo-seq) revealed discrete footprints of CENP-A chromatin assembled at telomeric locations on subsets of chromosomes. By modelling ALT activation, we show that epigenetic dysregulation due to ATRX loss and DNA hypomethylation facilitates the acquisition of these centromeric chromatin signatures. Functionally, interfering with HJURP-mediated CENP-A deposition compromises telomere integrity and ALT, leading to aberrant telomeric mitotic DNA synthesis (MiDAS). We propose that, while originally generated by illegitimate recombination, these centromeric signatures became integral by maintaining telomeric chromatin integrity in the unique context of ALT cancer cells.
DOI: 10.1038/s41586-026-10598-1
Source: https://www.nature.com/articles/s41586-026-10598-1
期刊信息
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504