<p id="P3">Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes
are multi-subunit
molecular machines that play vital roles in regulating genomic architecture and are
frequently disrupted in human cancer and developmental disorders. To date, the modular
organization and pathways of assembly of these chromatin regulators remain unknown,
presenting a major barrier to structural and functional determination. Here, we elucidate
the architecture and assembly pathway across three classes of mSWI/SNF complexes—canonical
BRGI/BRM-associated factor (BAF), polybromo-associated BAF (PBAF), and newly defined
ncBAF complexes—and define the requirement of each subunit for complex formation and
stability. Using affinity purification of endogenous complexes from mammalian and
<i>Drosophila</i> cells coupled with cross-linking mass spectrometry (CX-MS) and mutagenesis,
we uncover
three distinct and evolutionarily conserved modules, their organization, and the temporal
incorporation of these modules into each complete mSWI/SNF complex class. Finally,
we map human disease-associated mutations within subunits and modules, defining specific
topological regions that are affected upon subunit perturbation.
</p><p id="P4">Mapping assembly pathways for mSWI/ SNF remodeling complexes delineates
three distinct
organizational modules and contextualizes human disease mutations.
</p><p id="P5">
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