{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Howe J"],"funding":["National Institute of Health and Medical Research","Oregon State University","National Institutes of Health","NIGMS NIH HHS","NIH HHS"],"pagination":["4433-4442"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9748353"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["121(23)"],"pubmed_abstract":["Tumor suppressor p53 binding protein 1 (53BP1) is a scaffolding protein involved in poly-ADP ribose polymerase inhibitor hypersensitivity in BRCA1-negative cancers. 53BP1 plays a critical role in the DNA damage response and relies on its oligomerization to create foci that promote repair of DNA double-strand breaks. Previous work shows that mutation of either the oligomerization domain or the dynein light chain 8 (LC8)-binding sites of 53BP1 results in reduced accumulation of 53BP1 at double-strand breaks. Mutation of both abolishes focus formation almost completely. Here, we show that, contrary to current literature, 53BP1 contains three LC8-binding sites, all of which are conserved in mammals. Isothermal titration calorimetry measuring binding affinity of 53BP1 variants with LC8 shows that the third LC8-binding site has a high affinity and can bind LC8 in the absence of other sites. NMR titrations confirm that the third site binds LC8 even in variants that lack the other LC8-binding sites. The third site is the closest to the oligomerization domain of 53BP1, and its discovery would challenge our current understanding of the role of LC8 in 53BP1 function."],"journal":["Biophysical journal"],"pubmed_title":["Multivalent binding of the hub protein LC8 at a newly discovered site in 53BP1."],"pmcid":["PMC9748353"],"funding_grant_id":["S10 OD018518","R01 GM141733","R01GM141733","2014162","1S10OD018518"],"pubmed_authors":["Barbar E","Reardon P","Weeks A","Howe J"],"additional_accession":[]},"is_claimable":false,"name":"Multivalent binding of the hub protein LC8 at a newly discovered site in 53BP1.","description":"Tumor suppressor p53 binding protein 1 (53BP1) is a scaffolding protein involved in poly-ADP ribose polymerase inhibitor hypersensitivity in BRCA1-negative cancers. 53BP1 plays a critical role in the DNA damage response and relies on its oligomerization to create foci that promote repair of DNA double-strand breaks. Previous work shows that mutation of either the oligomerization domain or the dynein light chain 8 (LC8)-binding sites of 53BP1 results in reduced accumulation of 53BP1 at double-strand breaks. Mutation of both abolishes focus formation almost completely. Here, we show that, contrary to current literature, 53BP1 contains three LC8-binding sites, all of which are conserved in mammals. Isothermal titration calorimetry measuring binding affinity of 53BP1 variants with LC8 shows that the third LC8-binding site has a high affinity and can bind LC8 in the absence of other sites. NMR titrations confirm that the third site binds LC8 even in variants that lack the other LC8-binding sites. The third site is the closest to the oligomerization domain of 53BP1, and its discovery would challenge our current understanding of the role of LC8 in 53BP1 function.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2025-04-05T13:01:30.256Z","creation":"2025-04-05T13:01:30.256Z"},"accession":"S-EPMC9748353","cross_references":{"pubmed":["36335430"],"doi":["10.1016/j.bpj.2022.11.006"]}}