close
Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jun;51(6):1011-1023.
doi: 10.1038/s41588-019-0421-z. Epub 2019 May 20.

Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations

Gaetano Ivan Dellino  1   2 , Fernando Palluzzi  3   4 , Andrea Maria Chiariello  5 , Rossana Piccioni  3 , Simona Bianco  5 , Laura Furia  3 , Giulia De Conti  3 , Britta A M Bouwman  6 , Giorgio Melloni  3   7 , Davide Guido  8 , Luciano Giacò  3 , Lucilla Luzi  3 , Davide Cittaro  9 , Mario Faretta  3 , Mario Nicodemi  5   10 , Nicola Crosetto  6 , Pier Giuseppe Pelicci  11   12
Affiliations

Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations

Gaetano Ivan Dellino et al. Nat Genet. 2019 Jun.

Abstract

It is not clear how spontaneous DNA double-strand breaks (DSBs) form and are processed in normal cells, and whether they predispose to cancer-associated translocations. We show that DSBs in normal mammary cells form upon release of paused RNA polymerase II (Pol II) at promoters, 5' splice sites and active enhancers, and are processed by end-joining in the absence of a canonical DNA-damage response. Logistic and causal-association models showed that Pol II pausing at long genes is the main predictor and determinant of DSBs. Damaged introns with paused Pol II-pS5, TOP2B and XRCC4 are enriched in translocation breakpoints, and map at topologically associating domain boundary-flanking regions showing high interaction frequencies with distal loci. Thus, in unperturbed growth conditions, release of paused Pol II at specific loci and chromatin territories favors DSB formation, leading to chromosomal translocations.

PubMed Disclaimer

Comment in

Publication types

MeSH terms