Base excision repair hierarchy in eukaryotes: Intrinsically disordered region-mediated regulation of genomic...

Base excision repair (BER) in eukaryotes must navigate a crowded nuclear environment to locate rare lesions embedded in diverse chromatin contexts, such as nucleosomes, replication forks, and active promoters. Central to this sophisticated search are intrinsically disordered regions (IDRs) flanking the conserved catalytic cores of enzymes like OGG1, APE1, TDG, NEIL1, UNG2, and XRCC1. These IDRs act as biophysical tuners that govern BER dynamics by (i) regulating multi-state DNA target search through a non-linear balance of 3D encounters and 1D facilitated diffusion, (ii) modulating sampling across heterogeneous chromatin environments, and (iii) modulating the nucleation and decay of transient repair assemblies. While the chemistry of catalytic cores is well-defined, how IDRs quantitatively tune these kinetic search modes and scaffolded assemblies remains enigmatic. Recent single-molecule and live-cell imaging now allow for a transition from static, end-point readouts toward a high-resolution kinetic description of BER as a dynamic, hierarchical genomic surveillance system.