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

ABSTRACT: Mono-methylation of histone H4 lysine 20 (H4K20me1) is increasingly appreciated to be critical for regulating genomic DNA replication, cell cycle progression and DNA damage repair. How exactly H4K20me1 regulates these biological processes remains murky. Here, we report that an evolutionarily conserved tandem Tudor domain (TTD) in the BAH Domain And Coiled-Coil Containing 1 (BAHCC1) protein (BAHCC1_TTD) selectively reads H4K20me1 for facilitating the replication origin activation and efficient DNA replication. Our integrated biochemical, structural, genomic and cellular analyses demonstrated that BAHCC1_TTD preferentially recognizes H4K20me1 to promote the recruitment of BAHCC1 and its interacting partners, notably the Mini-chromosome Maintenance (MCM) complex, to the replication origin sites. Combined actions of the H4K20me1-reading BAHCC1 and the H4K20me2-reading Origin Recognition Complex (ORC) ensure optimal genomic loading of MCM complexes for facilitating DNA replication. Depletion of BAHCC1, or disruption of the BAHCC1_TTD:H4K20me1 interaction, reduces levels of H4K20me1 and MCM loading, leading to defects in replication and cell cycle progression. Together, this study identifies BAHCC1_TTD as a conserved effector transducing the H4K20me1 signals to the recruitment of MCM complexes for facilitating efficient DNA replication.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293272 | GEO | 2025/06/03

REPOSITORIES: GEO

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Project description:There are approximately 500 known origins of replication in the yeast genome, and the process by which DNA replication initiates at these locations is well understood. In particular, these sites are made competent to initiate replication by loading of the Mcm replicative helicase prior to the start of S phase; thus, "a site to which MCM is bound in G1" might be considered to provide an operational definition of a replication origin. By fusing a subunit of Mcm to micrococcal nuclease, a technique referred to as "Chromatin Endogenous Cleavage", we previously showed that known origins are typically bound by a single Mcm double hexamer, loaded adjacent to the ARS consensus sequence (ACS). Here we extend this analysis from known origins to the entire genome, identifying candidate Mcm binding sites whose signal intensity varies over at least 3 orders of magnitude. Published data quantifying the production of ssDNA during S phase showed clear evidence of replication initiation among the most abundant 1600 of these sites, with replication activity decreasing in concert with Mcm abundance and disappearing at the limit of detection of ssDNA. Three other hallmarks of replication origins were apparent among the most abundant 5,500 sites. Specifically, these sites (1) appeared in intergenic nucleosome-free regions that were flanked on one or both sides by well-positioned nucleosomes; (2) were flanked by ACSs; and (3) exhibited a pattern of GC skew characteristic of replication initiation. Furthermore, the high resolution of this technique allowed us to demonstrate a strong bias for detecting Mcm double-hexamers downstream rather than upstream of the ACS, which is consistent with the directionality of Mcm loading by Orc that has been observed in vitro. We conclude that DNA replication origins are at least 3-fold more abundant than previously assumed, and we suggest that replication may occasionally initiate in essentially every intergenic region. These results shed light on recent reports that as many as 15% of replication events initiate outside of known origins, and this broader distribution of replication origins suggest that S phase in yeast may be less distinct from that in humans than is widely assumed.

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

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