Congcong Tian, Qin Zhang, Jing Jia, Jiaqi Zhou, Ziwei Zhang, Srinivasu Karri, Jiuhang Jiang, Quinn Dickinson, Yuan Yao, Xiaorong Tang, Yuxin Huang, Ting Guo, Ziwei He, Zheng Liu, Yuan Gao, Xinran Yang, Yuchun Wu, Kui Ming Chan, Daoqin Zhang, Junhong Han, Chuanhe Yu, and Haiyun Gan

PNAS; May 7, 2024; 121 (20) e2400610121; https://doi.org/10.1073/pnas.2400610121

Significance

As faithful DNA replication is a crucial process for genetic inheritance, the accurate copying of epigenetic information is vital for maintaining cell lineage. It is well known that DNA polymerases are responsible for genomic DNA duplication. In this study, we have identified that Pol δ, one of the DNA polymerases, serves as a key chaperone for transferring parental histones to the lagging strand during DNA replication, assuring the faithful inheritance of epigenetic information carried by parental histone posttranslational modifications to the daughter cells. This finding reveals an exquisite process that Pol δ facilitates parental histone inheritance while replicating the lagging DNA strands.

Abstract

Chromatin replication is intricately intertwined with the recycling of parental histones to the newly duplicated DNA strands for faithful genetic and epigenetic inheritance. The transfer of parental histones occurs through two distinct pathways: leading strand deposition, mediated by the DNA polymerase ε subunits Dpb3/Dpb4, and lagging strand deposition, facilitated by the MCM helicase subunit Mcm2. However, the mechanism of the facilitation of Mcm2 transferring parental histones to the lagging strand while moving along the leading strand remains unclear. Here, we show that the deletion of Pol32, a nonessential subunit of major lagging-strand DNA polymerase δ, results in a predominant transfer of parental histone H3–H4 to the leading strand during replication. Biochemical analyses further demonstrate that Pol32 can bind histone H3–H4 both in vivo and in vitro. The interaction of Pol32 with parental histone H3–H4 is disrupted through the mutation of the histone H3–H4 binding domain within Mcm2. Our findings identify the DNA polymerase δ subunit Pol32 as a critical histone chaperone downstream of Mcm2, mediating the transfer of parental histones to the lagging strand during DNA replication.

See https://www.pnas.org/doi/10.1073/pnas.2400610121