Nuclear poly(A)-binding protein 1 is an ATM target and essential for DNA double-strand break repair.

Authors:
Ran Elkon
Ran Elkon
Tel Aviv University
Israel
Georgina D Barnabas
Georgina D Barnabas
Cancer Genetics Laboratory
Alejandro Pineiro Ugalde
Alejandro Pineiro Ugalde
The Netherlands Cancer Institute
London | United Kingdom
Reuven Agami
Reuven Agami
The Netherlands Cancer Institute
Netherlands
Tamar Geiger
Tamar Geiger
Tel Aviv University
Israel

Nucleic Acids Res 2018 Jan;46(2):730-747

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

The DNA damage response (DDR) is an extensive signaling network that is robustly mobilized by DNA double-strand breaks (DSBs). The primary transducer of the DSB response is the protein kinase, ataxia-telangiectasia, mutated (ATM). Here, we establish nuclear poly(A)-binding protein 1 (PABPN1) as a novel target of ATM and a crucial player in the DSB response. PABPN1 usually functions in regulation of RNA processing and stability. We establish that PABPN1 is recruited to the DDR as a critical regulator of DSB repair. A portion of PABPN1 relocalizes to DSB sites and is phosphorylated on Ser95 in an ATM-dependent manner. PABPN1 depletion sensitizes cells to DSB-inducing agents and prolongs the DSB-induced G2/M cell-cycle arrest, and DSB repair is hampered by PABPN1 depletion or elimination of its phosphorylation site. PABPN1 is required for optimal DSB repair via both nonhomologous end-joining (NHEJ) and homologous recombination repair (HRR), and specifically is essential for efficient DNA-end resection, an initial, key step in HRR. Using mass spectrometry analysis, we capture DNA damage-induced interactions of phospho-PABPN1, including well-established DDR players as well as other RNA metabolizing proteins. Our results uncover a novel ATM-dependent axis in the rapidly growing interface between RNA metabolism and the DDR.

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Source
http://dx.doi.org/10.1093/nar/gkx1240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778506PMC

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January 2018
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References

(Supplied by CrossRef)
DNA double-strand-break repair in higher eukaryotes and its role in genomic instability and cancer: cell cycle and proliferation-dependent regulation
Semin. Cancer Biol. 2016
DNA damage response: three levels of DNA repair regulation
Cold Spring Harb. Perspect. Biol. 2013
The repair and signaling responses to DNA double-strand breaks
Adv. Genet. 2013
DNA double-strand break repair in a cellular context
Clin. Oncol. (R. Coll. Radiol.) 2014

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