ORC binding to Heterochromatin Protein 1 through intrinsically disordered regions is required for heterochromatin structure and function

Phosphorylation alters the bulk chemical properties of Orc1 to tune DNA binding, phase separation, and heterochromatin partitioning

It is demonstrated that phosphorylation tunes the biochemical properties of the Orc1 IDR to control DNA binding, phase separation, and, consequentially, heterochromatin recruitment and suggests that localized dephosphorylation of the DNA binding Orc1 IDR may underlie recruitment of ORC to specific genomic loci.

Metazoan Orc6 Proteins Evolved Alternative Mechanisms for Association with the ORC Complex: Insights from Drosophila Modeling

This study analyzed specific residues within the C-terminal α11 helix that are critical for stable association of Orc6 with the ORC complex in Drosophila and proposed that this NLS drives human protein to the nucleus and compensates for weaker Orc6-ORC(1-5) interactions by increasing the nuclear concentration of Orc6 a...

Single-molecule chromatin tracing reveals a diversity of megabase heterochromatin domains

Chromosomes fold into distinct domains that regulate transcription, replication and repair. In addition to well-characterized topologically associating domains (TADs) and compartments, the diversity of heterochromatin domains remains poorly defined at the sequence level. Here, using single-molecule tracing of nascent h...

Intrinsically disordered regions navigate DNA replication licensing factors to specific genomic loci

Sites of DNA replication initiation are determined by binding of the Origin Recognition Complex (ORC, composed of Orc1-6) to specific genomic loci. Here, we determine the mechanism underlying site-specific binding of human Orc1. We find that Orc1’s Bromo-Adjacent Homology (BAH) domain functions as an avidity element, w...

Heterochromatin protein 1α acts as an essential stabilizer of chromatin packing domains

MacroH2A1 and H3K27me3 target cGAS to facultative heterochromatin to restrain innate immune activation

The DNA sensor cGAS is largely sequestered on chromatin in an inactive form, but how this state is regulated remains unclear. We show that cGAS preferentially binds nucleosomes containing the histone variant macroH2A1 (mH2A1) marked by H3K27me3 and H3K9me3. Cryo-EM reveals that cGAS selectively engages the mH2A1/H2B ac...