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2015 ; 1
(5
): e1500447
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Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights
gained from human genomics
#MMPMID26601204
Kadoch C
; Crabtree GR
Sci Adv
2015[Jun]; 1
(5
): e1500447
PMID26601204
show ga
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.