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Journal article
Nuclear poly(A)-binding protein 1 is an ATM target and essential for DNA double-strand break repair
Nucleic acids research, Vol.46(2), pp.730-747
25/Jan/2018
PMCID: PMC5778506
PMID: 29253183
Abstract
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.
Details
- Title
- Nuclear poly(A)-binding protein 1 is an ATM target and essential for DNA double-strand break repair
- Creators
- Michal Gavish-Izakson - Tel Aviv UniversityBhagya Bhavana Velpula - Tel Aviv UniversityRan Elkon - Tel Aviv UniversityRosario Prados-Carvajal - Universidad de SevillaGeorgina D Barnabas - Tel Aviv UniversityAlejandro Pineiro Ugalde - 972WIS_INST___7946c6d9-d8f5-4ce1-926c-300fa9199d1eReuven Agami - 972WIS_INST___7946c6d9-d8f5-4ce1-926c-300fa9199d1eTamar Geiger - Tel Aviv UniversityPablo Huertas - Universidad de SevillaYael Ziv - Tel Aviv UniversityYosef Shiloh - Tel Aviv University
- Resource Type
- Journal article
- Publication Details
- Nucleic acids research, Vol.46(2), pp.730-747; 25/Jan/2018
- Publisher
- Oxford University Press
- Language
- English
- DOI
- https://doi.org/10.1093/nar/gkx1240
- PMID
- 29253183
- PMCID
- PMC5778506
- Grant note
- We thank Thanos Halazonetis for the anti-53BP1 antibody and Sapir Schlam-Babayov for help and advice throughout this study. FUNDING Work in Y.S. laboratory is funded by research grants from the Dr Miriam and Sheldon G. Adelson Medical Research Foundation; The A-T Children's Project; The Israel Science Foundation (Joint ISF-NSFC Program with the National Natural Science Foundation of China); The Israel Cancer Research Fund; Work in P.H. lab was supported by R+D+I grant from the Spanish Ministry of Economy and Competitivity [SAF2013-43255-P]; ERC Starting Grant [DSBRECA]; PhD fellowship from the Spanish Ministry of Education (FPU to R.P.-C.); The R.A. lab is supported by NWO grant [NGI 93512001 to R.A.]; The Human Frontier Science Program [LT000640/2013 to A.P.U.]; The work in T.G. lab was supported by The I-CORE Program of the Planning and Budgeting Committee of the Israel Ministry of Education; Y.S. is a Research Professor of the Israel Cancer Research Fund. Funding for open access charge: research grant money.
- Record Identifier
- 993285427203596
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