Telomere Length Dynamics and the Evolution of Cancer Genome Architecture

Abstract

Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that bypass such signals during tumour progression, a critical length threshold is reached at which telomere dysfunction may ensue. Dysfunction of the telomere nucleoprotein complex can expose free chromosome ends to the DNA double-strand break (DSB) repair machinery, leading to telomere fusion with both telomeric and non-telomeric loci. The consequences of telomere fusions in promoting genome instability have long been appreciated through the breakage–fusion–bridge (BFB) cycle mechanism, although recent studies using high-throughput sequencing technologies have uncovered evidence of involvement in a wider spectrum of genomic rearrangements including chromothripsis. A critical step in cancer progression is the transition of a clone to immortality, through the stabilisation of the telomere repeat array. This can be achieved via the reactivation of telomerase, or the induction of the alternative lengthening of telomeres (ALT) pathway. Whilst telomere dysfunction may promote genome instability and tumour progression, by limiting the replicative potential of a cell and enforcing senescence, telomere shortening can act as a tumour suppressor mechanism. However, the burden of senescent cells has also been implicated as a driver of ageing and age-related pathology, and in the promotion of cancer through inflammatory signalling. Considering the critical role of telomere length in governing cancer biology, we review questions related to the prognostic value of studying the dynamics of telomere shortening and fusion, and discuss mechanisms and consequences of telomere-induced genome rearrangements.

Intriguing Relationships Between Cancer and Systemic Sclerosis: Role of the Immune System and Other Contributors

“…While telomere maintenance is complex as well as essential for cancer progression (78), deficient telomerase activity and telomere shortening have been both reported in SSc (79, 80). In another fibrotic condition, IPF, telomere shortening is also a potential contributor for the pathological process and reduction in telomere length of circulating leukocytes could even have an impact on overall mortality (81).…”

Molecular Pathogenesis of Hodgkin Lymphoma: Past, Present, Future

“…Its discovery in the 1980s was recognized by the reception of the 2009 Nobel Prize in Physiology of Medicine [ 45 , 46 , 47 , 48 ]. Telomerase activity was found to be higher in germline and stem cells and nearly absent in somatic cells, which explains the normally occurring telomeric shortening with each cell division [ 49 , 50 ]. In 1997, telomerase activity in cHL was detected for the first time by Brousset et al [ 51 ] and Bryan et al described the principle of alternative lengthening of telomeres (ALT), a telomerase-independent pathway able to maintain telomeric length in malignant tumors [ 52 ].…”

Heterogeneous Nuclear Ribonucleoproteins Involved in the Functioning of Telomeres in Malignant Cells

“…Relevant and important processes occur in normal and pathological tissues, including malignant tumors, and more than 50 reviews have been published in 2018 alone on these issues (for example, [14,15,16]). It is believed that several peculiarities (dysregulation) in the functioning and dynamics of telomeres exist in human malignant cells (HMCs) that are not present in normal cells [1,7,17,18,19]. Moreover, it has been shown that telomerase activity is either not defined or is detectable at low levels in normal cells [20,21,22].…”