Connecting Chromosomes, Crisis, and Cancer
Abstract
Cancer is a disease of impaired genome stability. The molecular forces that maintain genome integrity and sense altered chromosome structure are invariably subverted in cancer cells. Here, we explore the contrasting contributions of telomeres in the initiation and suppression of cancer and review the evidence supporting a role for telomere dysfunction as a mechanism driving the radical chromosomal aberrations that typify cancer genomes. Recent work suggests that passage of cells through crisis in the setting of deactivated DNA damage checkpoints provides a mutational mechanism that can generate the diverse genetic alterations required for cancer initiation. A greater understanding of telomere-induced crisis and the cell's crisis management mechanisms should guide the rational development of new therapeutics for cancer and other disorders.
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Fused chromosomes can initiate bridge-breakage-fusion cycles, causing more chromosome rearrangements and genomic instability that promote mitotic crisis.
“These fused chromosomes can initiate bridge–breakage–fusion cycles, causing more chromosome rearrangements and genomic instability that promote mitotic crisis [349,350].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [349]
Malignant progression requires a period similar to telomere crisis that can result in large-scale genome rearrangements commonly seen in tumors.
“These observations indicate that malignant progression requires a period similar to the telomere crisis that can result in large-scale genome rearrangements of the kind commonly seen in tumors [349,351].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [349]
Telomere attrition contributes to tumorigenesis by promoting genome instability.
“A large body of experimental evidence has demonstrated that telomere attrition contributes to tumorigenesis by promoting genome instability5.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [5]
Fusions are the basis of genomic instability associated with telomere dysfunction, leading to anaphase bridging, breakage and repair; repetition leads to aneuploidy and further fusions, and loss of heterozygosity or gene amplification could result in tumorigenesis.
“These fusions are the basis of genomic instability associated with telomere dysfunction as they lead to anaphase bridging, subsequent breakage and that requires further repair. Repetition of this fusion-bridge-breakage cycle leads to aneuploidy, further fusions and depending on how such DNA damage is resolved, it has been hypothesized that loss of heterozygosity or gene amplification could result”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [5]
Failure of checkpoints in pre-cancerous cells with critically short telomeres can lead to genomic instability through DNA end-to-end fusions and can promote cancer progression.
“In addition, failure of checkpoints in pre-cancerous cells with critically short telomeres can lead to genomic instability through DNA end-to-end fusions and can promote cancer progression (Maser and DePinho, 2002).”
From Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging (2015) · cites this paper as Maser and DePinho, 2002
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- Authors
- Maser, R. S., & DePinho, R. A.
- Affiliations
- Harvard University (US)
- Corresponding author
- DePinho, Ronald A.
- ORCID
- DePinho, Ronald A.
- Venue
- Science
- Published
- 2002-07-26
- Volume
- 297
- Issue
- 5581
- Pages
- 565-569
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2018369441
- Semantic Scholar
- fa9434acf68c373a39188715970e597fc9339bc9
- Cited by
- 561
- References
- 25
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 12 · 2023: 5 · 2022: 5 · 2021: 17 · 2020: 9 · 2019: 7 · 2018: 8 · 2017: 12 · 2016: 14 · 2015: 20 · 2014: 18 · 2013: 27 · 2012: 27
- FWCI
- 6.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- telomeres, telomere dysfunction, crisis, genome stability, DNA damage checkpoint, chromosomal instability, tumor initiation, tumor suppression, mutational mechanisms, cancer therapeutics
- MeSH terms
- Animals, Cell Cycle, Cell Division, Cell Transformation, Neoplastic, Cells, Cultured, DNA Damage, DNA Repair, Humans, Neoplasms, Genetic Therapy, Signal Transduction, Telomere, Disease Progression, Telomerase
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