Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion.

Jitendra K Meena,Karl Lenhard Rudolph,Johann M Kraus,Christine Beichler,Fabrizio D'Adda Di Fagagna,Christopher Bruhn,Aurora Cerutti,Hans A Kestler,Mukesh Kumar,Yohei Morita,Michael R Speicher,Zhao‐Qi Wang,Cagatay Günes

doi:10.15252/embj.201797470

Abstract

The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy-controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase in this process. The study shows that aneuploidy induces replication stress at telomeres leading to telomeric DNA damage and p53 activation. This results in p53/Rb-dependent, premature senescence of human fibroblast, and in the depletion of hematopoietic cells in telomerase-deficient mice. Endogenous telomerase expression in HSCs and enforced expression of telomerase in human fibroblasts are sufficient to abrogate aneuploidy-induced replication stress at telomeres and the consequent induction of premature senescence and hematopoietic cell depletion. Together, these results identify telomerase as an aneuploidy survival factor in mammalian cells based on its capacity to alleviate telomere replication stress in response to aneuploidy induction.

Highlights

CH2AX staining of IMR90 cells mentioned in the results section (page 1373, last sentence “. . . telomerase-negative BJ and IMR90 fibroblasts exhibited a strong accumulation of DNA damage at early passage after shRNA transduction (Fig 2A, C and D, Supplementary Fig S3A and B). . .” was not depicted in the paper, and the 53BP1 staining was performed only on the BJ cells
A repeat of the p-p53 Western blot was run on a separate gel using the same protein lysates and loading buffer
The Western blot for p21 in Fig 1D and the corresponding beta-actin control were run in parallel with the same protein lysates and the same loading on 2 separate gels; the gel probed for beta-actin was not shown in the original source data file of Fig 1D