9z04
Structure of human lymphoid-specific helicase HELLS in its auto-inhibitory state
Structural highlights
DiseaseHELLS_HUMAN ICF syndrome. The disease may be caused by variants affecting the gene represented in this entry. FunctionHELLS_HUMAN ATP-dependent chromatin remodeler that regulates chromatin accessibility, DNA methylation, and histone modifications. It facilitates de novo DNA methylation at repetitive sequences and promotes transcriptional silencing via recruitment of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), contributing to heterochromatin formation and repression of transposable elements (PubMed:30307408). Also involved in DNA repair by recruiting DNA damage response mediators to double-strand breaks in heterochromatin, promoting homologous recombination via RBBP8/CtIP-dependent end resection (PubMed:22946062, PubMed:31802118). During meiosis, it is recruited by PRDM9 to recombination hotspots, aiding chromatin opening (PubMed:32001511). Through these diverse roles, is crucial for processes such as development, differentiation, and genomic stability (PubMed:22946062, PubMed:31802118). Involved in regulation of the expansion or survival of lymphoid cells (By similarity).[UniProtKB:Q60848][1] [2] [3] [4] Publication Abstract from PubMedHelicase, Lymphoid Specific (HELLS), also known as Lymphoid-Specific Helicase (LSH), is a member of the SNF2 chromatin-remodeling family that regulates DNA methylation and heterochromatin organization. Unlike most chromatin remodelers, HELLS is catalytically inactive in its apo form and requires the DNA-binding protein CDCA7 for activation, though the underlying mechanism has remained unclear. Here, we combine biochemical, biophysical, and cryo-electron microscopy analyses to define the structural basis of HELLS autoinhibition. HELLS alone assembles into a hexameric (trimer of dimers) architecture stabilized by interactions between its N-terminal coiled-coil (CC) domain and ATPase Lobe-1, while ATPase Lobe-2 remains flexible and disengaged. The CC domain functions both as an oligomerization scaffold and as an autoinhibitory module that restricts catalytic activity. Binding of CDCA7 and DNA promotes formation of an active HELLS-CDCA7-DNA ternary complex. CDCA7 recognizes hemimethylated CpG dinucleotides in both B-form and non-B-form DNA and stimulates HELLS ATPase activity. Together, these findings reveal the mechanism of HELLS autoinhibition and its activation by CDCA7 and DNA, providing new insight into how the HELLS-CDCA7-DNA ternary complex maintains DNA methylation and heterochromatin integrity. Structure of human lymphoid-specific helicase HELLS in its autoinhibited state.,Kaur G, Ren R, Lee J, Horton JR, Zhang X, Gao Y, Chen T, Cheng X Nucleic Acids Res. 2026 Mar 19;54(6):gkag326. doi: 10.1093/nar/gkag326. PMID:41954988[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
