Citations 2
Phosphatidylinositol 3-phosphate promotes 53BP1 condensate-like assembly at DNA double-strand breaks
Xiong, Nan, Xu, Xuanqi, Xie, Yawen, Liang, Shikang , Liu, Yang, Yu, Cheng‐han , Mer, Georges , Huen, Michael Shing Yan, Xiong, Nan, Cui, Gaofeng , Ti, Shih-Chieh , Draviam, Viji M.
No container title available | April 22, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
53BP1 nuclear bodies are dynamic structures with properties resembling biomolecular condensates, but the molecular determinants that govern 53BP1 higher-order assembly at DNA double-strand breaks (DSBs) remain to be established. Here, we show that 53BP1 condensation is stimulated by phosphatidylinositol 3-phosphate (PI(3)P) in vitro through a highly specific interaction with its C-terminal tandem BRCT domain (tBRCT). Consequently, mutational inactivation of the 53BP1 tBRCT domain compromised PI(3)P binding and suppressed 53BP1 optodroplet formation in vivo. We further show that rapid 53BP1 clustering following DNA damage precedes its stable assembly on DSB-flanking chromatin, requires its tBRCT, and is suppressed by sequestration of nuclear PI(3)P. Taken together, our findings identify PI(3)P binding as a mechanism that promotes the formation and maturation of 53BP1 condensate-like assemblies on damaged chromatin.
Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules
Dodd, Daniel O , Mechaussier, Sabrina , Yeyati, Patricia L. , McPhie, Fraser , Anderson, Jacob R. , Khoo, Chen Jing , Shoemark, Amelia , Gupta, Deepesh Kumar , Attard, Thomas, Zariwala, Maimoona A. , Legendre, Marie , Bracht, Diana , Gui, Miao , Parry, David , Black, Holly A. , Mitri-Frangieh, Rana, Faucon, Catherine, Kaplan, Josseline, Megaw, Roly , Mohamed, Mai A., Aitken, Stuart , Gautier, Philippe , Reinholt, Finn R., Hirst, Robert A. , O’Callaghan, Chris, Bottier, Mathieu , Escudier, Estelle , Crowley, Suzanne , Descartes, Maria , Kenia, Priti , Amiel, Jeanne , Bacci, Giacomo Maria , Calogero, Claudia , Palazzo, Viviana , Tiberi, Lucia , Blümlein, Ulrike, Rogers, Andrew, Wenger, David A. , Fulton, Anne B. , Rosenfeld, Margaret , Holm, Ingrid A., Quigley, Alan J. , Murphy, Laura C. , Cassidy, Diane M. , Kriegsheim, Alex von , Partnership, Scottish Genomes, Network, Undiagnosed Diseases, Murris, Marlène , Hogg, Claire , Macleod, Kenneth , Urquhart, Don S. , Unger, Stefan , Amselem, Serge , Leigh, Margaret W. , Knowles, Michael R. , Mitchison, Hannah M. , Rozet, Jean‐Michel , Mill, Pleasantine , Gupta, Deepesh K , Wallmeier, Julia , Fassad, Mahmoud R , Tennant, Peter A , Meynert, Alison , Wheway, Gabrielle , Fares-Taie, Lucas , Black, Holly A , Patel, Mitali , McKie, Lisa , Megaw, Roly , Aitken, Stuart , Gautier, Philippe , Heimdal, Ketil , Bottier, Mathieu , Escudier, Estelle , Crowley, Suzanne , Descartes, Maria , Jabs, Ethylin W , Bacci, Giacomo Maria , Calogero, Claudia , Tiberi, Lucia , Wambach, Jennifer A , Wegner, Daniel J , Fulton, Anne B , Kenna, Margaret , Quigley, Alan , Hall, Emma A , Murphy, Laura C , Cassidy, Diane M , von Kriegsheim, Alex , Pasquier, Laurent , Murris, Marlène S , Chalmers, James D , Hogg, Claire , Macleod, Kenneth A , Urquhart, Don S , Unger, Stefan , Aitman, Timothy J , Leigh, Margaret W , Omran, Heymut , Mitchison, Hannah M , Brown, Alan , Marsh, Joseph A , Ti, Shih-Chieh , Horani, Amjad , Rozet, Jean-Michel , Perrault, Isabelle , Mill, Pleasantine , Dodd, Daniel O. , Mechaussier, Sabrina , Gatsogiannis, Christos , Holm, Ingrid A., Partnership, Scottish Genomes, Network, Undiagnosed Diseases, Papon, Jean‐François , Pasquier, Laurent , Chalmers, James D. , Omran, Heymut , Welburn, Julie P. I.
Science | April 25, 2024 | Volume: 384 | Issue: 6694 | Pages: No page available
Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type– and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.