期刊
GENES & DEVELOPMENT
卷 27, 期 15, 页码 1662-1679出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.218966.113
关键词
histone methyltransferase; H3 Lys 27 methylation; replication stress; replication elongation; ssDNA; replication origin
资金
- NIH [R01-GM087343, 1P41RR018627, R01-GM53572, R01-HG005119]
- National Natural Science Foundation of China [31071993]
- Fund of State Key Laboratory of Genetics Resources and Evolution [GREKF10-09]
- University of Michigan Rackham Graduate Student Research Grant
Replication of nuclear DNA occurs in the context of chromatin and is influenced by histone modifications. In the ciliate Tetrahymena thermophila, we identified TXR1, encoding a histone methyltransferase. TXR1 deletion resulted in severe DNA replication stress, manifested by the accumulation of ssDNA, production of aberrant replication intermediates, and activation of robust DNA damage responses. Paired-end Illumina sequencing of ssDNA revealed intergenic regions, including replication origins, as hot spots for replication stress in Delta TXR1 cells. Delta TXR1 cells showed a deficiency in histone H3 Lys 27 monomethylation (H3K27me1), while Delta EZL2 cells, deleting a Drosophila E(z) homolog, were deficient in H3K27 di- and trimethylation, with no detectable replication stress. A point mutation in histone H3 at Lys 27 (H3 K27Q) mirrored the phenotype of Delta TXR1, corroborating H3K27me1 as a key player in DNA replication. Additionally, we demonstrated interactions between TXR1 and proliferating cell nuclear antigen (PCNA). These findings support a conserved pathway through which H3K27me1 facilitates replication elongation.
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