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Sequential histone H1 N76/77 deamidation and K75 acetylation facilitate chromatin relaxation and genome stability by DNA repair

ABSTRACT: The formation of accessible chromatin around DNA double-strand breaks is essential for efficient repair. While the linker histone H1 is known to facilitate the higher-order chromatin compaction, the mechanisms by which H1 modifications regulate chromatin relaxation in response to DNA damage are unclear. Here, we demonstrate that the CTP synthase 1 (CTPS1)-catalyzed deamidation of H1 asparagine residues 76 and 77 triggers the sequential acetylation of lysine 75 following DNA damage, and this dual modification of H1 is associated with chromatin opening. Mechanistically, the histone acetyltransferase p300 has a preference for deamidated H1 as a substrate, establishing H1 deamidation as a prerequisite for subsequent acetylation. Moreover, high CTPS1 expression was found to be associated with resistance to cancer radiotherapy, both in mouse xenograft models and clinical cohorts. These findings provide new insights into how linker histones regulate dynamic chromatin alterations in the DNA damage response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288071 | GEO | 2025/02/03

REPOSITORIES: GEO

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