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. 2020 Mar 3;2(1):zcaa003. doi: 10.1093/narcan/zcaa003

Figure 4.

Figure 4.

Aberrant CDK12-regulated gene expression has pleiotropic role in onset of genome instability. The schema depicts multiple ways in which non-functional CDK12 causes genome instability. (Left) The premature transcription termination of many HR and DNA replication genes results in an inactive HR DNA repair pathway and G1/S progression defects. The subsequent onset of HR defects and replication stress contributes to genome instability in cells. In ovarian and prostate cancers with inactive CDK12, a parallel onset of HR defects and replication stress likely leads to the onset of a unique CDK12-specific genome instability phenotype, focal tandem duplications. (Right) Inactive CDK12 does not allow the release of 4E-BP1 from eIF4E, which leads to suboptimal translation of a subset of mRNAs, mainly CHK1 and several subunits of centrosome, centromere and kinetochore complexes. The subsequent mitotic defect is characterized by chromosome misalignment and segregation defects, which also contribute to cellular genome instability.