Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics

By Cigall Kadoch, G. Crabtree. Science Advances, 2015

789 citations recorded by the source corpus.

New human genetic findings paired with biochemical studies are challenging current thinking on the function of chromatin remodeling complexes. Over the past 4 years, nearly 100 exome sequencing studies have revealed the high frequency of mutations in the genes encoding the subunits of ATP-dependent chromatin remodelers in human cancer. Most of these mutations are within the genes encoding subunits of the BAF (Brg/Brahma-associated factors) or mSWI/SNF complex, which is one of two dozen predicted ATP-dependent chromatin remodeling complexes in mammals. Considering BAF complexes as a single entity, the 15 subunits encoded by 29 genes are mutated in >20% of human cancer, across a broad range of tumor types. These observations demonstrate that there is little redundancy in the oncogenic function of BAF complexes with the other remodeling complexes, underscoring their unique roles. Several important conclusions emerge from these genomic data: specific subunits appear to be mutated in specific cancers, highlighting tissue-specific protective roles; mutations can function as tumor suppressors or oncogenes; mutations can be homozygous or, more commonly, heterozygous, implying their dosage-sensitive roles in an unknown yet fundamental process used to suppress the genesis of cancer. These new human genetic findings paired with biochemical studies are challenging old ideas on how chromatin remodeling complexes function, generating new hypotheses with respect to their normal and oncogenic mechanisms and highlighting potential avenues for therapeutic intervention in human cancer.

Subfields: Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/fc6d99012b642d2cb0b4c2a7ac041cd95135268c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Luciano Di Croce
2. H. Bourbon
3. B. Schuettengruber
4. Giacomo Cavalli

In Pathology and Forensic Medicine

1. Giacomo Cavalli
2. H. Bourbon
3. B. Schuettengruber
4. Luciano Di Croce

Citations in the corpus

• Genome Regulation by Polycomb and Trithorax: 70 Years and Counting. (2017, positive): “Elegant biochemical, genetic, and molecular studies led to the discovery that mammalian homologs of SWI/SNF, BRM, and BRG1 form two distinct complexes, BAF and PBAF, each of which contains up to 15 additional subunits that arewell conserved during evolution (Table 1; Figure 1A) andwhich regulate chr”
• Transcriptional Addiction in Cancer (2017, neutral): “The positioning of nucleosomes on DNA can also influence gene control, for example by limiting access of TFs to regulatory sequences, and ATP-dependent remodeling complexes influence transcriptional states by mobilizing nucleosomes (Kadoch and Crabtree, 2015).”