Mechanistic insights into chromatin modulation by the "orphan" remodeler ATRX

Alpha-thalassemia/mental retardation syndrome X-linked protein (ATRX) is an ATP-dependent chromatin remodeler that performs diverse functions. The mechanism by which ATRX modulates chromatin is unknown. Here, our cryo-electron microscopy (cryo-EM) structure revealed that human ATRX recognizes the nucleosome through its C-terminal regions by embracing and unwrapping ∼18 base pair nucleosomal DNA near entry/exit sites in the presence of ADP⋅BeF₃. Strikingly, the DNA minor groove between super helical location (SHL)6 and SHL7 is profoundly deformed by a "pin-like" structure on the "poking helix" in ATRX, which intercalates the aromatic side chain of a phenylalanine into the base stacking. To translocate the DNA on the nucleosome, ATRX further utilizes a disordered insertion to contact the histone surface and a positively charged loop to bridge cross-gyre interactions. Both the "pin-like" structure and the histone-contacting region of ATRX were found to be essential for protecting cells from G-quadruplex DNA-induced stress, highlighting the importance of these features in ATRX-mediated chromatin remodeling.