Nature 447, 972-978 (2007) A citation (ref. 1) was inadvertently removed during revision of this Article, which also emphasized the potential importance of chro-matin modifications in innate immune responses.

Subunits of mammalian SWI/SNF (mSWI/SNF, also called BAF) complexes have recently been implicated as tumor suppressors in a number of human malignancies. To understand the full extent of their involvement, we conducted a proteomic analysis of purified endogenous mSWI/SNF complexes. Our studies revealed several new dedicated, stable subunits not found in the yeast SWI/SNF complex including Bcl7a, b and c, Bcl11a and b, Brd9 and SS18. Incorporating these novel members, we determined the frequency of mSWI/SNF subunit mutations in recent exome- and whole-genome sequencing studies of primary human tumors. Surprisingly, mSWI/SNF subunits are mutated in 19.6% of all human tumors reported in 44 exome sequencing studies. Our analysis suggests that specific subunits protect against cancer in specific tissues. In addition, we find that mutations to more than one subunit, which we define as a type of compound heterozygosity, are prevalent in certain cancers. Our studies demonstrate that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer and that in contrast to other known tumor suppressors and oncogenes surveyed, mSWI/SNF is broadly mutated, similar to TP53. Thus, proper functioning of these polymorphic chromatin regulatory complexes may constitute a major mechanism of human tumor suppression.

Macromolecular assemblies that regulate chromatin structure using the energy of ATP hydrolysis have critical roles in development, cancer, and stem cell biology. The ATPases of this family are encoded by 27 human genes and are usually associated with several other proteins that are stable, non-exchangeable subunits. One fundamental mechanism used by these complexes is thought to be the movement or exchange of nucleosomes to regulate transcription. However, recent genetic studies indicate that chromatin remodelers may also be involved in regulating other aspects of chromatin structure during many cellular processes. The SWI/SNF family in particular appears to have undergone a substantial change in subunit composition and mechanism coincident with the evolutionary advent of multicellularity and the appearance of linking histones. The differential usage of this greater diversity of mammalian BAF subunits is essential for the development of specific cell fates, including the progression from pluripotency to multipotency to committed neurons. Recent human genetic screens have revealed that BRG1, ARID1A, BAF155, and hSNF5 are frequently mutated in tumors, indicating that BAF complexes also play a critical role in the initiation or progression of cancer. The mechanistic bases underlying the genetic requirements for BAF and other chromatin remodelers in development and cancer are relatively unexplored and will be a focus of this review.