CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation
© 2019, The Author(s). Cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and selectively affects the expression of genes involved in the DNA damage response (DDR) and mRNA processing. Yet, the mechanisms underlyi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/135185 |
| _version_ | 1826201702551781376 |
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| author | Krajewska, Malgorzata Dries, Ruben Grassetti, Andrew V Dust, Sofia Gao, Yang Huang, Hao Sharma, Bandana Day, Daniel S Kwiatkowski, Nicholas Pomaville, Monica Dodd, Oliver Chipumuro, Edmond Zhang, Tinghu Greenleaf, Arno L Yuan, Guo-Cheng Gray, Nathanael S Young, Richard A Geyer, Matthias Gerber, Scott A George, Rani E |
| author_facet | Krajewska, Malgorzata Dries, Ruben Grassetti, Andrew V Dust, Sofia Gao, Yang Huang, Hao Sharma, Bandana Day, Daniel S Kwiatkowski, Nicholas Pomaville, Monica Dodd, Oliver Chipumuro, Edmond Zhang, Tinghu Greenleaf, Arno L Yuan, Guo-Cheng Gray, Nathanael S Young, Richard A Geyer, Matthias Gerber, Scott A George, Rani E |
| author_sort | Krajewska, Malgorzata |
| collection | MIT |
| description | © 2019, The Author(s). Cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and selectively affects the expression of genes involved in the DNA damage response (DDR) and mRNA processing. Yet, the mechanisms underlying such selectivity remain unclear. Here we show that CDK12 inhibition in cancer cells lacking CDK12 mutations results in gene length-dependent elongation defects, inducing premature cleavage and polyadenylation (PCPA) and loss of expression of long (>45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlates with an increased number of intronic polyadenylation sites, a feature especially prominent among DDR genes. Phosphoproteomic analysis indicated that CDK12 directly phosphorylates pre-mRNA processing factors, including those regulating PCPA. These results support a model in which DDR genes are uniquely susceptible to CDK12 inhibition primarily due to their relatively longer lengths and lower ratios of U1 snRNP binding to intronic polyadenylation sites. |
| first_indexed | 2024-09-23T11:55:25Z |
| format | Article |
| id | mit-1721.1/135185 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:55:25Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1351852021-10-28T04:09:27Z CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation Krajewska, Malgorzata Dries, Ruben Grassetti, Andrew V Dust, Sofia Gao, Yang Huang, Hao Sharma, Bandana Day, Daniel S Kwiatkowski, Nicholas Pomaville, Monica Dodd, Oliver Chipumuro, Edmond Zhang, Tinghu Greenleaf, Arno L Yuan, Guo-Cheng Gray, Nathanael S Young, Richard A Geyer, Matthias Gerber, Scott A George, Rani E © 2019, The Author(s). Cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and selectively affects the expression of genes involved in the DNA damage response (DDR) and mRNA processing. Yet, the mechanisms underlying such selectivity remain unclear. Here we show that CDK12 inhibition in cancer cells lacking CDK12 mutations results in gene length-dependent elongation defects, inducing premature cleavage and polyadenylation (PCPA) and loss of expression of long (>45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlates with an increased number of intronic polyadenylation sites, a feature especially prominent among DDR genes. Phosphoproteomic analysis indicated that CDK12 directly phosphorylates pre-mRNA processing factors, including those regulating PCPA. These results support a model in which DDR genes are uniquely susceptible to CDK12 inhibition primarily due to their relatively longer lengths and lower ratios of U1 snRNP binding to intronic polyadenylation sites. 2021-10-27T20:11:09Z 2021-10-27T20:11:09Z 2019 2019-07-18T13:51:42Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135185 en 10.1038/s41467-019-09703-y Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Krajewska, Malgorzata Dries, Ruben Grassetti, Andrew V Dust, Sofia Gao, Yang Huang, Hao Sharma, Bandana Day, Daniel S Kwiatkowski, Nicholas Pomaville, Monica Dodd, Oliver Chipumuro, Edmond Zhang, Tinghu Greenleaf, Arno L Yuan, Guo-Cheng Gray, Nathanael S Young, Richard A Geyer, Matthias Gerber, Scott A George, Rani E CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation |
| title | CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation |
| title_full | CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation |
| title_fullStr | CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation |
| title_full_unstemmed | CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation |
| title_short | CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation |
| title_sort | cdk12 loss in cancer cells affects dna damage response genes through premature cleavage and polyadenylation |
| url | https://hdl.handle.net/1721.1/135185 |
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