Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors
Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors
ABSTRACT The activation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape replicative senescence and apoptosis. Paediatric brain tumors frequently exhibit Alternative Lengthening of Telomere (ALT) as active TMM, but the mechanisms involved in the induction of ALT in brain tumor cells are not clear. Here, we report a model of juvenile zebrafish brain tumor that progressively develops ALT. We discovered that reduced expression of tert and increase in Terra expression precedes ALT development. Additionally, tumors show persistent telomeric DNA damage and loss of heterochromatin marks at chromosome ends. Surprisingly, expression of telomerase reverts ALT features. Comparative analysis of gene expression after the rescue of ALT with telomerase and analysis of telomerase positive paediatric brain cancers showed increase of telomeric heterochromatin and maintenance of telomere length compared to ALT tumors, with reduced expression of genes of the pre-replicative complex as hallmark. Thus our study identifies telomere maintenance mechanisms as major drivers of telomeric DNA replication and chromatin status in brain cancers.
Pagani Francesca、Idilli Aurora Irene、Kerschbamer Emanuela、Poliani Pietro Luigi、Mione Maria Caterina、Cusanelli Emilio、Piazza Silvano、Berardinelli Francesco、Cayuela Mar¨aa Luisa、Bernab¨| Manuel
Pathology, Department of Molecular and Translational Medicine, University of BresciaDepartment of Cellular, Computational and Integrative Biology ¨C CIBIO, University of TrentoDepartment of Cellular, Computational and Integrative Biology ¨C CIBIO, University of TrentoPathology, Department of Molecular and Translational Medicine, University of BresciaDepartment of Cellular, Computational and Integrative Biology ¨C CIBIO, University of TrentoDepartment of Cellular, Computational and Integrative Biology ¨C CIBIO, University of TrentoDepartment of Cellular, Computational and Integrative Biology ¨C CIBIO, University of TrentoDepartment of Science, University of Rome ?°Roma Tre?±Telomerase, Cancer and Aging, Dept. of Surgery, Instituto Murciano de Investigaci¨?n Biosanitaria-ArrixacaTelomerase, Cancer and Aging, Dept. of Surgery, Instituto Murciano de Investigaci¨?n Biosanitaria-Arrixaca
肿瘤学基础医学分子生物学
Pagani Francesca,Idilli Aurora Irene,Kerschbamer Emanuela,Poliani Pietro Luigi,Mione Maria Caterina,Cusanelli Emilio,Piazza Silvano,Berardinelli Francesco,Cayuela Mar¨aa Luisa,Bernab¨| Manuel.Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/718551.点此复制
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