Page 57 - Hormel Report 2021

While cellular DNA replication was not grossly affected during the mitotic cell cycle by asymmetric nucleosome partitioning, we found that silenced mating type locus was significantly disturbed in the Dpb3/ Dpb4 and Mcm2 mutant yeast cells. Interestingly, parental histone in the double mutant (both Dpb3 deletion and Mcm2 mutant) shows no obvious strand bias. It indicates that Pol-epsilon and MCM helicase mediated parental histone transfer work on independent ways. In addi- tion, the homologous recombination efficiency in the double mutant is significantly reduced compared to wild type cells. It indicates the cell chromatin structure were altered in the double mutant cells. Together our studies thus suggest that parental nucleosome segregation is determined by a balance of replisome-intrinsic histone chaperone activities. Modulation of individual histone chaperone activities at the fork may therefore provide a potential mechanism for the asymmetric distribution of epigenetic marks to determine cell fate in development.
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Current research projects:
1) Regulation mechanism of parental histone assembly in yeast.
2) Functional analysis on epigenetic inheritance of DNA polymerase and MCM helicase
3) New approaches to study DNA replication coupled process.
Figure 1: Parental histone (H3-H4)2 tetramer transfer model and the phenotype of histone transfer chaperone mutants. (1) the parental histone (H3-H4)2 tetramer transfer is not random but biased toward the replication lagging strand; (2) DNA polymerase ε and MCM helicase mediate the parental histone transfer to the replication leading and lagging strands, respectively; and that (3) parental histone chaperone mutants shows instable epigenetic inheritance and lower homologous recombination (HR) frequency.
Publications:
• Serra-Cardona A, Yu C, Zhang X, Hua X, Yao Y, Zhou J, Gan H, Zhang Z. A mechanism for Rad53 to couple leading- and lagging-strand DNA synthesis under replication stress in budding yeast. Proc Natl Acad Sci U S A 2021; 118. PMCID:34531325
• Yu C, Gan H, Serra-Cardona A, Zhang L, Gan S, Sharma S, Johansson E, Chabes A, Xu RM, Zhang Z. A mechanism for preventing asymmetric histone segregation onto replicating DNA strands. Science 2018; 361: 1386-9. PMCID:30115745
• Gan H, Yu C, Devbhandari S, Sharma S, Han J, Chabes A, Remus D, Zhang Z. Checkpoint Kinase Rad53 Couples Leading- and Lagging-Strand DNA Synthesis under Replication Stress. Mol Cell 2017; 68: 446-55 e3. PMCID:29033319