@article{cfde98e5d522434fa56b0b788da65226,
title = "Transcriptional elongation requires DNA break-induced signalling",
abstract = "We have previously shown that RNA polymerase II (Pol II) pause release and transcriptional elongation involve phosphorylation of the factor TRIM28 by the DNA damage response (DDR) kinases ATM and DNA-PK. Here we report a significant role for DNA breaks and DDR signalling in the mechanisms of transcriptional elongation in stimulus-inducible genes in humans. Our data show the enrichment of TRIM28 and γH2AX on serum-induced genes and the important function of DNA-PK for Pol II pause release and transcriptional activation-coupled DDR signalling on these genes. γH2AX accumulation decreases when P-TEFb is inhibited, confirming that DDR signalling results from transcriptional elongation. In addition, transcriptional elongation-coupled DDR signalling involves topoisomerase II because inhibiting this enzyme interferes with Pol II pause release and γH2AX accumulation. Our findings propose that DDR signalling is required for effective Pol II pause release and transcriptional elongation through a novel mechanism involving TRIM28, DNA-PK and topoisomerase II.",
author = "Heeyoun Bunch and Lawney, {Brian P.} and Lin, {Yu Fen} and Aroumougame Asaithamby and Ayesha Murshid and Wang, {Yaoyu E.} and Chen, {Benjamin P C} and Calderwood, {Stuart K.}",
note = "Funding Information: We appreciate D. J. Taatjes at the University of Colorado, Boulder for critical reading and helpful comments for the manuscript and S. Buratowski at Harvard Medical School for interest in our research and reading the manuscript. We thank M. A. Stevenson at Beth Israel Deaconess Medical Center (BIDMC) and B. D. Price at Dana Farber Cancer Institute for discussions and W. Wei laboratory in BIDMC for sharing equipment. We are grateful to T. Westerling and M. Brown for providing with ChIP-seq library construction. We thank S. Gupta and T. Volkert in the Whitehead Institute Genomic Technology Core and S. Motola and S. Levine in the MIT Biomicro Center for the generation and sequencing of the ChIP libraries. H.B. thanks M. Cross at BIDMC for administrative support and D. Bunch, D. Verrengia, K. Perkins, R. S. Baker and Brookline small group members, and P.S.C. for loving encouragement throughout the work. This study was supported by grants from the US National Institute of Health (NIH) RO1CA166677 to B.P.C.C and NIH 2RO1CA047407-21 and 1RO1CA176326 and the Harvard Joint Center for Radiation Therapy to S.K.C. and H.B.",
year = "2015",
month = dec,
day = "16",
doi = "10.1038/ncomms10191",
language = "English (US)",
volume = "6",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}