H4S47 O-GlcNAcylation regulates the activation of mammalian replication origins
H4S47 O-GlcNAcylation regulates the activation of mammalian replication origins
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DOI：
10.1038/s41594-023-00998-6
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发表时间：
2023-05
影响因子：
16.8
通讯作者：
Yingying Zou;Jiayao Pei;Haizhen Long;Liting Lan;K. Dong;Tingting Wang;Ming Li;Zhexuan Zhao;Li-Chang Zhu;Gangxuan Zhang;Xin Jin;Yang Wang;Zengqi Wen;Min Wei;Yunpeng Feng
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文献类型：
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作者：
Yingying Zou;Jiayao Pei;Haizhen Long;Liting Lan;K. Dong;Tingting Wang;Ming Li;Zhexuan Zhao;Li-Chang Zhu;Gangxuan Zhang;Xin Jin;Yang Wang;Zengqi Wen;Min Wei;Yunpeng Feng
真核细胞中遗传信息的传递和维持依赖于整个基因组的忠实复制。在每一轮分裂中，过量的复制起始被许可，只有一小部分被激活，在染色质的背景下产生双向复制分叉。然而，真核生物的复制起源是如何被选择性激活的，这一点仍然难以捉摸。在这里，我们证明了o - glcnac转移酶（OGT）通过催化h4s47o - glcnac酰化来增强复制起始。H4S47突变会损害dbf4依赖性蛋白激酶（DDK）在染色质上的募集，导致复制解旋酶迷你染色体维持（MCM）复合体磷酸化降低和DNA解绕受损。我们的短新生链测序结果进一步证实了h4s47o - glcn酰化在起源激活中的重要性。我们提出h4s47o - glcnac酰化通过促进MCM磷酸化来指导起源激活，这可能揭示了染色质环境对复制效率的控制。
The transmission and maintenance of genetic information in eukaryotic cells relies on the faithful duplication of the entire genome. In each round of division, excessive replication origins are licensed, with only a fraction activated to give rise to bi-directional replication forks in the context of chromatin. However, it remains elusive how eukaryotic replication origins are selectively activated. Here we demonstrate thatO-GlcNAc transferase (OGT) enhances replication initiation by catalyzing H4S47O-GlcNAcylation. Mutation of H4S47 impairs DBF4-dependent protein kinase (DDK) recruitment on chromatin, causing reduced phosphorylation of the replicative helicase mini-chromosome maintenance (MCM) complex and compromised DNA unwinding. Our short nascent-strand sequencing results further confirm the importance of H4S47O-GlcNAcylation in origin activation. We propose that H4S47O-GlcNAcylation directs origin activation through facilitating MCM phosphorylation, and this may shed light on the control of replication efficiency by chromatin environment.