Dicentric chromosomes are formed by the fusion of dysfunctional telomeres during telomere crisis. Intact dicentrics persist through mitosis and form DNA bridges, which induce nuclear envelope failures resulting in the accumulation of Three prime repair exonuclease 1 (
) and cyclic GMP-AMP synthase (
) on the bridge DNA. Parts of the dicentric chromosome that are present in the DNA bridge undergo TREX1-mediated resection and extensive fragmentation. The fragmented chromosome undergoes haphazard repair, yielding a highly rearranged chromothripsis chromosome. Chromothripsis-associated breakpoints frequently display kataegis. Nuclear envelope failures at DNA bridges may result in a cGAS-dependent pro-inflammatory response.
Mutations in the telomerase reverse transcriptase (
) promoter drive telomerase reactivation through the creation of a GABP transcription factor binding site. Recently identified, recurrent mutations in the TERT 5′ untranslated region (
) associate with longer telomere length in clear cell renal cell carcinomas and are hypothesized to induce telomerase reactivation via inactivation of MAX-MAD1 transcriptional repression.
Telomerase reactivation heals dysfunctional telomeres to restore genomic stability and to provide a path out of telomere crisis