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

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2018

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Gavish-Izakson, Michal
Velpula, Bhagya Bhavana
Elkon, Ran
Prados-Carvajal, Rosario
Barnabas, Georgina D
Ugalde, Alejandro Pineiro
Agami, Reuven
Geiger, Tamar
Huertas, Pablo
Ziv, Yael

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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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Ataxia Telangiectasia Mutated Proteins
Cell Line, Tumor
DNA
DNA Breaks, Double-Stranded
DNA Repair
G2 Phase Cell Cycle Checkpoints
HeLa Cells
Humans
Nuclear Proteins
Phosphorylation
Poly(A)-Binding Protein I
Protein Binding
Protein Interaction Maps
RNA Interference

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