CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation

Malgorzata Krajewska; Ruben Dries; Andrew V. Grassetti; Sofia Dust; Yang Gao; Hao Huang; Bandana Sharma; Daniel S. Day; Nicholas Kwiatkowski; Monica Pomaville; Oliver Dodd; Edmond Chipumuro; Tinghu Zhang; Arno L. Greenleaf; Guo Cheng Yuan; Nathanael S. Gray; Richard A. Young; Matthias Geyer; Scott A. Gerber; Rani E. George

doi:10.1038/s41467-019-09703-y

CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation

Malgorzata Krajewska
, Ruben Dries
, Andrew V. Grassetti
, Sofia Dust
, Yang Gao
, Hao Huang
, Bandana Sharma
, Daniel S. Day
, Nicholas Kwiatkowski
, Monica Pomaville
, Oliver Dodd
, Edmond Chipumuro
, Tinghu Zhang
, Arno L. Greenleaf
, Guo Cheng Yuan
, Nathanael S. Gray
, Richard A. Young
, Matthias Geyer
, Scott A. Gerber
, Rani E. George

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	1757
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09703-y
Publication status	Published - 1 Dec 2019
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-019-09703-y

Cite this

Krajewska, M., Dries, R., Grassetti, A. V., Dust, S., Gao, Y., Huang, H., Sharma, B., Day, D. S., Kwiatkowski, N., Pomaville, M., Dodd, O., Chipumuro, E., Zhang, T., Greenleaf, A. L., Yuan, G. C., Gray, N. S., Young, R. A., Geyer, M., Gerber, S. A., & George, R. E. (2019). CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation. Nature Communications, 10(1), Article 1757. https://doi.org/10.1038/s41467-019-09703-y

@article{563c477c170048bc831a6b396b03ac94,

title = "CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation",

abstract = "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.",

author = "Malgorzata Krajewska and Ruben Dries and Grassetti, \{Andrew V.\} and Sofia Dust and Yang Gao and Hao Huang and Bandana Sharma and Day, \{Daniel S.\} and Nicholas Kwiatkowski and Monica Pomaville and Oliver Dodd and Edmond Chipumuro and Tinghu Zhang and Greenleaf, \{Arno L.\} and Yuan, \{Guo Cheng\} and Gray, \{Nathanael S.\} and Young, \{Richard A.\} and Matthias Geyer and Gerber, \{Scott A.\} and George, \{Rani E.\}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-09703-y",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Krajewska, M, Dries, R, Grassetti, AV, Dust, S, Gao, Y, Huang, H, Sharma, B, Day, DS, Kwiatkowski, N, Pomaville, M, Dodd, O, Chipumuro, E, Zhang, T, Greenleaf, AL, Yuan, GC, Gray, NS, Young, RA, Geyer, M, Gerber, SA & George, RE 2019, 'CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation', Nature Communications, vol. 10, no. 1, 1757. https://doi.org/10.1038/s41467-019-09703-y

TY - JOUR

T1 - CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation

AU - Krajewska, Malgorzata

AU - Dries, Ruben

AU - Grassetti, Andrew V.

AU - Dust, Sofia

AU - Gao, Yang

AU - Huang, Hao

AU - Sharma, Bandana

AU - Day, Daniel S.

AU - Kwiatkowski, Nicholas

AU - Pomaville, Monica

AU - Dodd, Oliver

AU - Chipumuro, Edmond

AU - Zhang, Tinghu

AU - Greenleaf, Arno L.

AU - Yuan, Guo Cheng

AU - Gray, Nathanael S.

AU - Young, Richard A.

AU - Geyer, Matthias

AU - Gerber, Scott A.

AU - George, Rani E.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85064432363

U2 - 10.1038/s41467-019-09703-y

DO - 10.1038/s41467-019-09703-y

M3 - Article

C2 - 30988284

AN - SCOPUS:85064432363

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1757

ER -

CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this