Researchers from Nankai University and Tsinghua University have published new findings on the effects of DNA–histone cross-links (DHCs) on genome stability. The study, which appears in Protein & Cell, examines how a single covalent bond between DNA and histone proteins can affect nucleosome behavior.
The team used click chemistry to engineer nucleosomes with a specific DNA–histone cross-link. According to their results, this modification does not change the overall structure of the nucleosome but makes it significantly more rigid and stable. The cross-linked nucleosomes resisted disassembly even under high-salt and high-temperature conditions.
Functionally, the presence of a single DHC was found to halt both thermally induced sliding of nucleosomes and ATP-dependent remodeling by the chromatin remodeler SNF2h. In transcription assays using SP6 RNA polymerase, DHC formation blocked transcription elongation within nucleosomes, causing premature termination about 15 base pairs before the cross-link site. The researchers noted that this effect is due to an inability of RNA polymerase to move the nucleosome along DNA rather than physical obstruction.
Additionally, DHCs were shown to make histones highly resistant to proteolytic degradation, indicating that these lesions may avoid conventional DNA repair mechanisms.
The authors state: "Together, these findings establish DNA–histone cross-links as a highly toxic and persistent form of DNA damage that rigidifies nucleosomes, impairs chromatin remodeling, and obstructs transcription." They add: "This study provides the first systematic analysis of DHC effects on nucleosome behavior in vitro and offers new insights into how covalent DNA–histone coupling may influence genome stability and epigenetic regulation in living cells."
