BAHCC1 binds H4K20me1 to facilitate the MCM complex loading and DNA replication

Dongxu Li, Zhi-Min Zhang, Liu Mei, Yao Yu, Yiran Guo, Samuel G. Mackintosh, Jianbin Chen, David F. Allison, Arum Kim, Aaron J. Storey, Ricky D. Edmondson, Stephanie D. Byrum, Alan J. Tackett, Ling Cai, Jeanette G. Cook (), Jikui Song () and Gang Greg Wang ()
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Dongxu Li: University of North Carolina at Chapel Hill
Zhi-Min Zhang: Riverside
Liu Mei: University of North Carolina at Chapel Hill
Yao Yu: Duke University School of Medicine
Yiran Guo: Duke University School of Medicine
Samuel G. Mackintosh: University of Arkansas for Medical Sciences
Jianbin Chen: Riverside
David F. Allison: University of North Carolina at Chapel Hill
Arum Kim: Duke University School of Medicine
Aaron J. Storey: University of Arkansas for Medical Sciences
Ricky D. Edmondson: University of Arkansas for Medical Sciences
Stephanie D. Byrum: University of Arkansas for Medical Sciences
Alan J. Tackett: University of Arkansas for Medical Sciences
Ling Cai: Duke University School of Medicine
Jeanette G. Cook: University of North Carolina at Chapel Hill
Jikui Song: Riverside
Gang Greg Wang: University of North Carolina at Chapel Hill

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Mono-methylation of histone H4 lysine 20 (H4K20me1) regulates DNA replication, cell cycle progression and DNA damage repair. How exactly H4K20me1 regulates these biological processes remains unclear. Here, we report that an evolutionarily conserved tandem Tudor domain (TTD) in BAHCC1 (BAHCC1TTD) selectively reads H4K20me1 for facilitating replication origin activation and DNA replication. Our biochemical, structural, genomic and cellular analyses demonstrate that BAHCC1TTD preferentially recognizes H4K20me1 to promote the recruitment of BAHCC1 and its interacting partners, notably Mini-chromosome Maintenance (MCM) complex, to replication origin sites. Combined actions of the H4K20me1-reading BAHCC1 and the H4K20me2-reading Origin Recognition Complex (ORC) ensure genomic loading of MCM for replication. Depletion of BAHCC1, or disruption of the BAHCC1TTD:H4K20me1 interaction, reduces H4K20me1 levels and MCM loading, leading to defects in replication origin activation and cell cycle progression. In summary, this study identifies BAHCC1TTD as an effector transducing H4K20me1 signals into MCM recruitment to promote DNA replication.

Date: 2025
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DOI: 10.1038/s41467-025-61284-1

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