{"doi":"10.7554/elife.22900","title":"Mutational phospho-mimicry reveals a regulatory role for the XRCC4 and XLF C-terminal tails in modulating DNA bridging during classical non-homologous end joining","abstract":"<jats:p>XRCC4 and DNA Ligase 4 (LIG4) form a tight complex that provides DNA ligase activity for classical non-homologous end joining (the predominant DNA double-strand break repair pathway in higher eukaryotes) and is stimulated by XLF. Independently of LIG4, XLF also associates with XRCC4 to form filaments that bridge DNA. These XRCC4/XLF complexes rapidly load and connect broken DNA, thereby stimulating intermolecular ligation. XRCC4 and XLF both include disordered C-terminal tails that are functionally dispensable in isolation but are phosphorylated in response to DNA damage by DNA-PK and/or ATM. Here we concomitantly modify the tails of XRCC4 and XLF by substituting fourteen previously identified phosphorylation sites with either alanine or aspartate residues. These phospho-blocking and -mimicking mutations impact both the stability and DNA bridging capacity of XRCC4/XLF complexes, but without affecting their ability to stimulate LIG4 activity. Implicit in this finding is that phosphorylation may regulate DNA bridging by XRCC4/XLF filaments.</jats:p>","journal":"eLife","year":2017,"id":37096,"datarank":1.5875890465281048,"base_score":3.7612001156935624,"endowment":3.7612001156935624,"self_citation_contribution":0.5641800173540344,"citation_network_contribution":1.0234090291740705,"self_endowment_contribution":0.5641800173540344,"citer_contribution":1.0234090291740705,"corpus_percentile":null,"corpus_rank":null,"citation_count":42,"citer_count":38,"citers_with_citation_signal":32,"citers_with_endowment":32,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":186628,"name":"Aurélie 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Cancer","grant_id":"SFI20121205867","title":null},{"funder_name":"U.S. Public Health Service","grant_id":"AI048758","title":null},{"funder_name":"Institut National Du Cancer","grant_id":"PLBIO13-099","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI048758","title":null},{"funder_name":"Institut National du 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Repair Mechanisms","CRISPR and Genetic Engineering","Cancer therapeutics and mechanisms","Medicine","Biology","0301 basic medicine","0303 health sciences","03 medical and health sciences","Amino Acid Substitution","DNA","DNA End-Joining Repair","DNA Mutational Analysis","DNA Repair Enzymes","DNA-Binding Proteins","Humans","Phosphorylation","Protein Binding","Protein Processing, Post-Translational"],"mesh_terms":["DNA","DNA Mutational Analysis","DNA-Binding Proteins","Humans","Phosphorylation","Protein Binding","Protein Processing, Post-Translational","Amino Acid Substitution","DNA Repair Enzymes","DNA End-Joining Repair"],"keywords":["DNA ligase","DNA repair protein XRCC4","Non-homologous end joining","DNA repair","Biology","DNA","Cell biology","Genetics","DNA mismatch repair","Genes","Human","Biochemistry","chromosomes","Nhej","Xrcc4","Xlf","DNA End-Joining Repair","QH301-705.5","Science","Q","DNA Mutational Analysis","R","[SDV] Life Sciences [q-bio]","DNA-Binding Proteins","DNA Repair Enzymes","Amino Acid Substitution","Medicine","Humans","Biology (General)","Phosphorylation","Protein Processing, Post-Translational","Protein Binding"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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