|Title||Structural variant evolution after telomere crisis.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Dewhurst SM, Yao X, Rosiene J, Tian H, Behr J, Bosco N, Takai KK, de Lange T, Imielinski M|
|Date Published||2021 04 07|
|Keywords||Cell Line, Chromosomal Instability, Chromothripsis, Fibroblasts, Genome, Genomic Instability, Humans, Lung, Metaphase, Models, Biological, Neoplasms, Telomere|
Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of experimental telomere crisis identified in previous studies. We examine the spectrum of structural variants (SVs) instigated by natural telomere crisis. Eight spontaneous post-crisis clones did not show prominent patterns of BFB cycles or chromothripsis. Their crisis-induced genome rearrangements varied from infrequent simple SVs to more frequent and complex SVs. In contrast, BFB cycles and chromothripsis occurred in MRC5 fibroblast clones that escaped telomere crisis after CRISPR-controlled telomerase activation. This system revealed convergent evolutionary lineages altering one allele of chromosome 12p, where a short telomere likely predisposed to fusion. Remarkably, the 12p chromothripsis and BFB events were stabilized by independent fusions to chromosome 21. The data establish that telomere crisis can generate a wide spectrum of SVs implying that a lack of BFB patterns and chromothripsis in cancer genomes does not indicate absence of past telomere crisis.
|Alternate Journal||Nat Commun|
|PubMed Central ID||PMC8027843|
|Grant List||R01 AG016642 / AG / NIA NIH HHS / United States |
R35 CA210036 / CA / NCI NIH HHS / United States
Related Faculty:Marcin Imielinski, M.D., Ph.D.