Phosphoinositide Variant Fuels 53BP1 Oligomerization and Higher-Order Assembly in the DNA Damage Response
XIONG, N.; Cui, G.; Xu, X.; Xie, Y.; Ti, S.-C.; liang, s.; Draviam, V. M.; Liu, Y.; Yu, C.-h.; Mer, G.; Huen, m. S. Y.
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53BP1 nuclear bodies are dynamic and are endowed with properties that resemble biomolecular condensates, but molecular determinants that underlie transition of 53BP1 oligomerisation to its higher-order assembly at DNA double-strand breaks (DSBs) remain to be established. We found that 53BP1 condensation is stimulated by phosphatidylinositol 3-phosphates (PI(3)Ps) in vitro, and is effected via its C-terminal phospho-binding BRCTs. Consistently, mutational inactivation of 53BP1 BRCTs not only compromised PI(3)P binding, but also suppressed its ability to undergo optodroplet formation in vivo. We further show that swift 53BP1 oligomerisation following DNA damage precedes its stable assembly on DSB-flanking chromatin, requires its BRCT domain, and is suppressed by sequestration of nuclear PI(3)Ps. Taken together, we propose that PI(3)P binding underlies maturation of 53BP1 higher-order assembly on the damaged chromatin.
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