Transcriptional elongation requires DNA break-induced signalling.

Nat Commun 2015 Dec 16;6:10191. Epub 2015 Dec 16.

Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.

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.

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http://dx.doi.org/10.1038/ncomms10191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703865PMC
December 2015
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References

(Supplied by CrossRef)

PB Rahl et al.
Cell 2010

S Nechaev et al.
Science 2010

GW Muse et al.
Nat. Genet. 2007

LJ Core et al.
Science 2008

J Zeitlinger et al.
Genes Dev. 2007

AC Seila et al.
Science 2008

K Adelman et al.
Nat. Rev. Genet. 2012

J Zeitlinger et al.
Nat. Genet. 2007

JQ Wu et al.
Genome Biol. 2008

CH Wu et al.
Genes Dev. 2003

BM Peterlin et al.
Mol. Cell 2006

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