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Ref Type Journal Article
PMID (24554720)
Authors Joshi PM, Sutor SL, Huntoon CJ, Karnitz LM
Title Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors.
Journal Vol Issue Date Pages Journal Short Title
The Journal of biological chemistry 289 13 2014 Mar 28 9247-53 J Biol Chem
URL
Abstract Text Mutations in the tumor suppressors BRCA1 and BRCA2, which encode proteins that are key participants in homologous recombination (HR) repair, occur in ∼20% of high grade serous ovarian cancers. Although only 20% of these tumors have mutations in BRCA1 and BRCA2, nearly 50% of these tumors have defects in HR. Notably, however, the underlying genetic defects that give rise to HR defects in the absence of BRCA1 and BRCA2 mutations have not been fully elucidated. Here we show that the recurrent somatic CDK12 mutations identified in ovarian cancers impair the catalytic activity of this kinase, which is involved in the transcription of a subset of genes, including BRCA1 and other DNA repair genes. Furthermore, we show that disabling CDK12 function in ovarian cancer cells reduces BRCA1 levels, disrupts HR repair, and sensitizes these cells to the cross-linking agents melphalan and cisplatin and to the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888). Taken together, these findings suggest that many CDK12 mutations are an unrecognized cause of HR defects in ovarian cancers.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
CDK12 NCBI CRK7|CRKR|CRKRS CDK12, cyclin dependent kinase 12, is a key regulator of transcription elongation, regulates the expression of genes involved in DNA repair, and is required for the maintenance of genomic stability (PMID: 24554720; PMID: 22012619). Loss and/or inactivation of CDK12 has been commonly observed in many solid tumor types, including prostate (PMID: 29906450, PMID: 31640893), breast, ovarian, endometrial, uterine (PMID: 30104286), and is a likely tumor suppressor (PMID: 30319007). Tumor suppressor
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
CDK12 A88fs frameshift loss of function - predicted CDK12 A88fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 88 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). A88fs has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of A88 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 D877N missense loss of function CDK12 D877N lies within the protein kinase domain of the Cdk12 protein (UniProt.org). D877N confers a loss of function to Cdk12 as demonstrated by loss of kinase activity in in vitro assays (PMID: 24662513, PMID: 24554720), and decreased transcriptional activity as a chimeric protein in a luciferase assay (PMID: 25712099).
CDK12 E647Kfs*8 frameshift loss of function - predicted CDK12 E647Kfs*8 indicates a shift in the reading frame starting at amino acid 647 and terminating 8 residues downstream causing a premature truncation of the 1490 amino acid Cdk12 protein (UniProt.org). E647Kfs*8 has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of E647 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 E72fs frameshift loss of function - predicted CDK12 E72fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 72 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). E72fs has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of E72 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 E928fs frameshift loss of function CDK12 E928fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 928 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). E928fs confers a loss of function to the Cdk12 protein as demonstrated by an inability to interact with CycK in vitro and reduced homologous recombination repair activity in cell culture (PMID: 25712099), and loss of kinase activity in an in vitro assay (PMID: 24554720).
CDK12 F89Sfs*3 frameshift loss of function - predicted CDK12 F89Sfs*3 indicates a shift in the reading frame starting at amino acid 89 and terminating 3 residues downstream causing a premature truncation of the 1490 amino acid Cdk12 protein (UniProt.org). F89Sfs*3 has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of F89 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 G909R missense loss of function CDK12 G909R lies within the protein kinase domain of the Cdk12 protein (UniProt.org). G909R confers a loss of function to the Cdk12 protein as demonstrated by its inability to restore Cdk12 function in Cdk12 depleted cells and by loss of activity in reporter assays (PMID: 24554720, PMID: 25712099).
CDK12 H111fs frameshift loss of function - predicted CDK12 H111fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 111 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). H111fs has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of H111 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 K46fs frameshift loss of function - predicted CDK12 K46fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 46 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). K46fs has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of K46 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 K756R missense loss of function CDK12 K756R lies within the protein kinase domain of the Cdk12 protein (UniProt.org). K756R results in decreased Cdk12 kinase activity in an in vitro assay and results in decreased homologous repair as demonstrated by failure to restore Rad51 foci formation in Cdk12-depleted cells in culture (PMID: 24554720).
CDK12 L122* nonsense loss of function - predicted CDK12 L122* results in a premature truncation of the Cdk12 protein at amino acid 122 of 1490 (UniProt.org). L122* has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of L122 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 P335fs frameshift loss of function - predicted CDK12 P335fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 335 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). P335fs has not been characterized, however, due to the effects of truncation mutations downstream of P335 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 P58fs frameshift loss of function - predicted CDK12 P58fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 58 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). P58fs has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of P58 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 P683Qfs*70 frameshift loss of function - predicted CDK12 P683Qfs*70 indicates a shift in the reading frame starting at amino acid 683 and terminating 70 residues downstream causing a premature truncation of the 1490 amino acid Cdk12 protein (UniProt.org). P683Qfs*70 has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of P683 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 Q602* nonsense loss of function - predicted CDK12 Q602* results in a premature truncation of the Cdk12 protein at amino acid 602 of 1490 (UniProt.org). Q602* has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of Q602 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 R204fs frameshift loss of function - predicted CDK12 R204fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 204 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). R204fs has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of R204 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 R271* nonsense loss of function - predicted CDK12 R271* results in a premature truncation of the Cdk12 protein at amino acid 271 of 1490 (UniProt.org). R271* has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of R271 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 R882L missense loss of function - predicted CDK12 R882L lies within the protein kinase domain of the Cdk12 protein (PMID: 22512864). R882L results in decreased Cdk12-mediated transcriptional activation, downregulation of DNA damage response genes (PMID: 25712099), and decreased kinase activity in cultured cells (PMID: 25712099) and an in vitro assay (PMID: 24554720), but induces proliferation similar to wild-type Cdk12 in one of two tested cell lines in culture (PMID: 29533785), and therefore is predicted to lead to a loss of Cdk12 protein function.
CDK12 S133Kfs*24 frameshift loss of function - predicted CDK12 S133Kfs*24 indicates a shift in the reading frame starting at amino acid 133 and terminating 24 residues downstream causing a premature truncation of the 1490 amino acid Cdk12 protein (UniProt.org). S133Kfs*24 has not been characterized, however, due to the effects of other truncation mutations downstream of S133 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 S343fs frameshift loss of function - predicted CDK12 S343fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 343 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). S343fs has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of S343 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 S587Ffs*54 frameshift loss of function - predicted CDK12 S587Ffs*54 indicates a shift in the reading frame starting at amino acid 587 and terminating 54 residues downstream causing a premature truncation of the 1490 amino acid Cdk12 protein (UniProt.org). S587Ffs*54 has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of S587 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 S62fs frameshift loss of function - predicted CDK12 S62fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 62 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). S62fs has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of S62 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 S785fs frameshift loss of function - predicted CDK12 S785fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 785 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). S785fs has not been biochemically characterized, however, due to the effects of truncation mutations downstream of S785 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 T212fs frameshift loss of function - predicted CDK12 T212fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 212 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). T212fs has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of T212 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 Y279* nonsense loss of function - predicted CDK12 Y279* results in a premature truncation of the Cdk12 protein at amino acid 279 of 1490 (UniProt.org). Y279* has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of Y279 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
CDK12 Y319fs frameshift loss of function - predicted CDK12 Y319fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 319 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). Y319fs has not been characterized, however, due to the effects of other truncation mutations downstream of Y319 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CDK12 dec exp ovarian cancer sensitive Cisplatin Preclinical Actionable In a preclinical study, the depletion of CDK12 in an ovarian cancer cell line by siRNAs resulted in the depletion of BRCA1 and sensitized the cells to the cross-linking agents Alkeran (melphalan), Platinol (cisplatin), and the PARP inhibitor veliparib (ABT-888) (PMID: 24554720). 24554720
CDK12 dec exp ovarian cancer sensitive Melphalan Preclinical Actionable In a preclinical study, the depletion of CDK12 in an ovarian cancer cell line by siRNAs resulted in the depletion of BRCA1 and sensitized the cells to the cross-linking agents Alkeran (melphalan), Platinol (cisplatin), and the PARP inhibitor veliparib (ABT-888) (PMID: 24554720). 24554720
CDK12 dec exp ovarian cancer sensitive Veliparib Preclinical - Cell culture Actionable In a preclinical study, the depletion of CDK12 in an ovarian cancer cell line by siRNAs resulted in the depletion of BRCA1 and sensitized the cells to the cross-linking agents Alkeran (melphalan), Platinol (cisplatin), and the PARP inhibitor, Veliparib (ABT-888) (PMID: 24554720). 24554720