DNA损伤,染色质 z-bio 2025-06-04 3512

　　The mechanism of histone H1 deamidation acetylation cascade modification in regulating chromatin looseness and genomic stability

　　Supported by the Major Project of the National Natural Science Foundation of China (Grant No. 32090030), Professor Zhu Weiguo's team from Shenzhen University discovered that deamidation modifications at positions 76 and 77 (H1N76/77) of asparagine in histone H1 play a crucial role in the early stages of DNA damage response (DDR). They revealed that deamidation modifications of H1N76/77 regulate chromatin remodeling by promoting acetylation of adjacent site H1K75 through a cascade reaction, thereby promoting the recruitment of damage repair factors. The research findings were published online on April 16th in the top international academic journal Nature under the title "Histone H1 deamidation facilities for chromatin relaxation for DNA repair". Paper link: https://doi.org/10.1038/s41586-025-08835-0

　　Chromatin looseness is a prerequisite for recruiting DNA damage repair factors in the early stage of DDR, and histone acetylation at DNA double strand breaks is crucial for chromatin looseness. However, the regulatory mechanism of histone acetylation in the early stages of DNA damage response, as well as whether other types of histone modifications are involved in chromatin opening, have long been key scientific questions that have plagued this field. Connecting histone H1 is one of the most important regulatory proteins for chromatin tight folding and a key button for maintaining nucleosome integrity. Although there have been reports showing that H1 can participate in DDR by recruiting chromatin remodeling proteins and repair factors, its specific mechanism of action in regulating chromatin looseness is still unclear, and whether specific conformational changes or post-translational modifications occur remains to be elucidated.

　　The research team led by Professor Zhu Weiguo found that after DNA double strand breaks occur, the asparagine residues (Asn76 and Asn77) at positions 76 and 77 of histone H1 undergo specific deamidation catalyzed by CTPS1 (cytosine triphosphate synthase), which in turn promotes acetylation of the lysine residue (Lys75) adjacent to position 75. The study also found that histone acetyltransferase p300 has significant substrate preference for deamidated H1, indicating that deamidation modification promotes subsequent acetylation modification events. Due to the fact that the 75th lysine of H1 is located within the spherical domain of histone H1, which is also the main functional domain for binding to DNA, acetylation at this site leads to a weakening of the binding force between histone H1 and DNA, resulting in the loosening of nucleosomes and chromatin and facilitating the recruitment of key proteins for DNA damage repair to repair broken DNA at the site of DNA damage.

　　This study suggests that the lysine at position 75, asparagine at positions 76 and 77 of histone H1 may form a specific "switch" that controls chromatin tightness. This discovery provides detailed data for understanding how chromatin dynamically changes under cellular stress, and also lays a theoretical foundation for the precise target design of tumor radiotherapy and chemotherapy.