Year: 2026
Type: preprint
Abstract: DNA damage repair in eukaryotes occurs within the context of chromatin, where nucleosomes can limit access of repair enzymes to damaged DNA. AP endonucleases are essential components of the base excision repair (BER) pathway, yet how their activity is regulated on nucleosomal substrates remains poorly understood. Here, we show that chromatin remodelers can directly stimulate AP endonuclease–mediated incision of nucleosomal DNA through a mechanism that is distinct from canonical nucleosome sliding. We find that the INO80 chromatin remodeler enhances AP-site incision by human and yeast AP endonucleases in an ATP-dependent or ATP-independent manner, depending on lesion position, and that this stimulatory effect is conserved in eukaryotes but absent for bacterial endonuclease IV. Despite their distinct modes of nucleosome engagement, both INO80 and the single-subunit remodeler CHD1 promote AP-site incision on nucleosomes, even when productive DNA translocation is impaired by the presence of lesions. Our data indicate that remodeler binding, coupled to ATP hydrolysis, is sufficient to induce local DNA distortions or transient unwrapping that increase lesion accessibility without requiring nucleosome sliding. Together, these findings reveal a previously unappreciated mode of chromatin remodeler function in BER and suggest that chromatin remodelers facilitate DNA repair by directly enhancing access of repair enzymes to damaged nucleosomal DNA.
Source: Preprints.org
Institution: Stony Brook University
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7125975287