Classical non-homologous end-joining pathway utilizes nascent RNA for error-free double-strand break repair of transcribed genes

Anirban Chakraborty, Nisha Tapryal, Tatiana Venkova, Nobuo Horikoshi, Raj K. Pandita, Altaf H. Sarker, Partha S. Sarkar, Tej K. Pandita and Tapas K. Hazra ()
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Anirban Chakraborty: Sealy Center for Molecular Medicine, University of Texas Medical Branch
Nisha Tapryal: Sealy Center for Molecular Medicine, University of Texas Medical Branch
Tatiana Venkova: Sealy Center for Molecular Medicine, University of Texas Medical Branch
Nobuo Horikoshi: The Houston Methodist Research Institute
Raj K. Pandita: The Houston Methodist Research Institute
Altaf H. Sarker: Lawrence Berkeley National Laboratory
Partha S. Sarkar: University of Texas Medical Branch
Tej K. Pandita: The Houston Methodist Research Institute
Tapas K. Hazra: Sealy Center for Molecular Medicine, University of Texas Medical Branch

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract DNA double-strand breaks (DSBs) leading to loss of nucleotides in the transcribed region can be lethal. Classical non-homologous end-joining (C-NHEJ) is the dominant pathway for DSB repair (DSBR) in adult mammalian cells. Here we report that during such DSBR, mammalian C-NHEJ proteins form a multiprotein complex with RNA polymerase II and preferentially associate with the transcribed genes after DSB induction. Depletion of C-NHEJ factors significantly abrogates DSBR in transcribed but not in non-transcribed genes. We hypothesized that nascent RNA can serve as a template for restoring the missing sequences, thus allowing error-free DSBR. We indeed found pre-mRNA in the C-NHEJ complex. Finally, when a DSB-containing plasmid with several nucleotides deleted within the E. coli lacZ gene was allowed time to repair in lacZ-expressing mammalian cells, a functional lacZ plasmid could be recovered from control but not C-NHEJ factor-depleted cells, providing important mechanistic insights into C-NHEJ-mediated error-free DSBR of the transcribed genome.

Date: 2016
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DOI: 10.1038/ncomms13049

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