Acidic patch histone mutations and their effects on nucleosome remodeling

Abstract

Structural and biochemical studies have identified a histone surface on each side of the nucleosome disk termed ‘the nucleosome acidic patch' that acts as a regulatory hub for the function of numerous nuclear proteins, including ATP-dependent chromatin complexes (remodelers). Four major remodeler subfamilies, SWI/SNF, ISWI, CHD, and INO80, have distinct modes of interaction with one or both nucleosome acidic patches, contributing to their specific remodeling outcomes. Genome-wide sequencing analyses of various human cancers have uncovered high-frequency mutations in histone coding genes, including some that map to the acidic patch. How cancer-related acidic patch histone mutations affect nucleosome remodeling is mainly unknown. Recent advances in in vitro chromatin reconstitution have enabled access to physiologically relevant nucleosomes, including asymmetric nucleosomes that possess both wild-type and acidic patch mutant histone copies. Biochemical investigation of these substrates revealed unexpected remodeling outcomes with far-reaching implications for alteration of chromatin structure. This review summarizes recent findings of how different remodeler families interpret wild-type and mutant acidic patches for their remodeling functions and discusses models for remodeler-mediated changes in chromatin landscapes as a consequence of acidic patch mutations.

Testis-specific H2BFWT disrupts nucleosome integrity through reductions of DNA-histone interactions

“…The acidic patch is well known to be involved in chromatin formation and protein-histone interactions, which include several chromatin remodeling factors and histone PTM modifying enzymes 42 . It is reported that acidic patch mutations can alter the function of chromatin remodelers 43 . The amino acid substitution from the negatively charged glutamate (E) in H2BE105 to the neutral glutamine (Q) in H2BFWTQ126 likely weakens the acidic patch.…”

(mis)-Targeting of SWI/SNF complex(es) in cancer

“…Many tumor suppressors proteins like TP53, MYC, Retinoblastoma (Rb), and BRCA1 interact with various SWI/SNF subunits [ 112 – 118 ]. Furthermore, more than 40% of P53 mutants bring about their effect by modulating SWI/SNF activity or recruitment to chromatin targets [ 117 , 119 , 120 ]. Similarly, MYC binds to various components of SWI/SNF and also regulates the expression of SWI/SNF subunits themselves [ 112 , 113 ].…”

Conformational switching of Arp5 subunit differentially regulates INO80 chromatin remodeling

“…The acidic pocket represents a crucial binding site on the nucleosome, characterized by a negatively charged depression. It serves as binding site for various chromatin-associated factors, including viral proteins (35), histone modifiers (36,37) and ATP-dependent chromatin remodelers (29,(38)(39)(40)(41). Interactions at this site play pivotal roles in regulating transcription, DNA repair and other genomic processes (41)(42)(43)(44).…”

“…It serves as binding site for various chromatin-associated factors, including viral proteins (35), histone modifiers (36,37) and ATP-dependent chromatin remodelers (29,38–41). Interactions at this site play pivotal roles in regulating transcription, DNA repair and other genomic processes (41–44).…”