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

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.

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

“…Replication stress arises in CIN cells due to impaired replication fork progression prompted by unrepaired DNA damage, topological stress or limiting nucleotides (Burrell et al, 2013; Ichijimaet al, 2010; Meena et al, 2015). If sustained for long periods it can lead to incompletely duplicated chromosomes that could undergo fragmentation or generate chromatin bridges, which in turn sustain chromosome rearrangements or tetraploidy (Burrell et al, 2013; Donley and Thayer, 2013; Russo et al, 2015).…”

“…DNA damage as an outcome of CIN is well documented (Ganem and Pellman, 2012; Hayashi and Karlseder, 2013; Janssen et al,2011; Meena et al, 2015; Ohashi et al, 2015) and can occur through multiple non-exclusive mechanisms. Because aneuploidy is a state of unbalanced karyotype, levels of proteins essential for DNA replication, condensation, repair or cell division are also expected to be unbalanced, which in turn could promote the induction of DNA damage and replication defects (Holland and Cleveland, 2012b; Meena et al, 2015; Nicholson and Cimini, 2015).…”

“…Because aneuploidy is a state of unbalanced karyotype, levels of proteins essential for DNA replication, condensation, repair or cell division are also expected to be unbalanced, which in turn could promote the induction of DNA damage and replication defects (Holland and Cleveland, 2012b; Meena et al, 2015; Nicholson and Cimini, 2015). Yeast cells, aneuploid for one single chromosome, show higher rates of point mutations and mitotic recombinations (Sheltzer et al, 2011).…”

“…Yeast cells, aneuploid for one single chromosome, show higher rates of point mutations and mitotic recombinations (Sheltzer et al, 2011). Telomerase expression in aneuploid mammalian cells abrogates aneuploidy-induced telomere replication stress and also decreases aneuploidy-induced DNA damage accumulation (Meena et al, 2015). …”

Shwachman-Diamond Syndrome Protein SBDS Maintains Human Telomeres by Regulating Telomerase Recruitment

“…The core telomerase complex is made up of the reverse transcriptase TERT and the RNA component hTR/TERC (Feng et al, 1995; Greider and Blackburn, 1985; Lingner et al, 1997). In human somatic cells, which normally have low or non-detectable telomerase activity, telomeres shorten gradually with each cell division, and cells with critically short telomeres may eventually undergo senescence or programmed cell death (Cao et al, 2011; Ló-pez-Otín et al, 2013; Martínez and Blasco, 2015; Meena et al, 2015). Highly proliferative and continuously dividing cells on the other hand, such as stem cells and cancer cells, often maintain high telomerase activity or reactivate the telomerase (Kim et al, 1994).…”