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Structural variant evolution after telomere crisis.

ABSTRACT: 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.

SUBMITTER: Dewhurst SM

PROVIDER: S-EPMC8027843 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recent advances in our structural understanding of telomerase and telomere-associated proteins have contributed significantly to elucidating the molecular mechanisms of telomere maintenance. The structures of telomerase TERT domains have provided valuable insights into how experimentally identified conserved motifs contribute to the telomerase reverse transcriptase reaction. Additionally, structures of telomere-associated proteins in a variety of organisms have revealed that, across evolution, telomere-maintenance mechanisms employ common structural elements. For example, the single-stranded 3' overhang of telomeric DNA is specifically and tightly bound by an OB-fold in nearly all species, including ciliates (TEBP and Pot1a), fission yeast (SpPot1), budding yeast (Cdc13), and humans (hPOT1). Structures of the yeast Cdc13, Stn1, and Ten1 proteins demonstrated that telomere maintenance is regulated by a complex that bears significant similarity to the RPA heterotrimer. Similarly, proteins that specifically bind double-stranded telomeric DNA in divergent species use homeodomains to execute their functions (human TRF1 and TRF2 and budding yeast ScRap1). Likewise, the conserved protein Rap1, which is found in budding yeast, fission yeast, and humans, contains a structural motif that is known to be critical for protein-protein interaction. In addition to revealing the common underlying themes of telomere maintenance, structures have also elucidated the specific mechanisms by which many of these proteins function, including identifying a telomere-specific domain in Stn1 and how the human TRF proteins avoid heterodimerization. In this review, we summarize the high-resolution structures of telomerase and telomere-associated proteins and discuss the emergent common structural themes among these proteins. We also address how these high-resolution structures complement biochemical and cellular studies to enhance our understanding of telomere maintenance and function.

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Structural variant evolution after telomere crisis.

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