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Congratulations to BB Grad Student Jesse Howe, for this paper published in Biophysical Journal!
53BP1 is a key player in the DNA double strand break repair pathway. Previous literature reports only 2 LC8 binding sites in 53BP1, which are important to recruitment of 53BP1 to sites of DNA damage. Here, we report a third LC8 binding site in 53BP1 and characterize the binding of 53BP1 to LC8 using a suite of biophysical techniques.
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.
Read the full article here: https://www.cell.com/biophysj/fulltext/S0006-3495(22)00904-3#relatedArticles