| RRC ID |
78781
|
| 著者 |
Adell MAY, Klockner TC, Höfler R, Wallner L, Schmid J, Markovic A, Martyniak A, Campbell CS.
|
| タイトル |
Adaptation to spindle assembly checkpoint inhibition through the selection of specific aneuploidies.
|
| ジャーナル |
Genes Dev
|
| Abstract |
Both the presence of an abnormal complement of chromosomes (aneuploidy) and an increased frequency of chromosome missegregation (chromosomal instability) are hallmarks of cancer. Analyses of cancer genome data have identified certain aneuploidy patterns in tumors; however, the bases behind their selection are largely unexplored. By establishing time-resolved long-term adaptation protocols, we found that human cells adapt to persistent spindle assembly checkpoint (SAC) inhibition by acquiring specific chromosome arm gains and losses. Independently adapted populations converge on complex karyotypes, which over time are refined to contain ever smaller chromosomal changes. Of note, the frequencies of chromosome arm gains in adapted cells correlate with those detected in cancers, suggesting that our cellular adaptation approach recapitulates selective traits that dictate the selection of aneuploidies frequently observed across many cancer types. We further engineered specific aneuploidies to determine the genetic basis behind the observed karyotype patterns. These experiments demonstrated that the adapted and engineered aneuploid cell lines limit CIN by extending mitotic duration. Heterozygous deletions of key SAC and APC/C genes recapitulated the rescue phenotypes of the monosomic chromosomes. We conclude that aneuploidy-induced gene dosage imbalances of individual mitotic regulators are sufficient for altering mitotic timing to reduce CIN.
|
| 巻・号 |
37(5-6)
|
| ページ |
171-190
|
| 公開日 |
2023-3-1
|
| DOI |
10.1101/gad.350182.122
|
| PII |
gad.350182.122
|
| PMID |
36859339
|
| PMC |
PMC10111865
|
| MeSH |
Aneuploidy
Chromosomal Instability / genetics
Humans
Karyotype
M Phase Cell Cycle Checkpoints* / genetics
Mitosis
Neoplasms* / genetics
Spindle Apparatus / genetics
|
| リソース情報 |
| ヒト・動物細胞 |
EEB(RCB2345) |
