H3K9me3 demethylase Kdm4d facilitates the formation of pre-initiative complex and regulates DNA replication

Abstract

DNA replication is tightly regulated to occur once and only once per cell cycle. How chromatin, the physiological substrate of DNA replication machinery, regulates DNA replication remains largely unknown. Here we show that histone H3 lysine 9 demethylase Kdm4d regulates DNA replication in eukaryotic cells. Depletion of Kdm4d results in defects in DNA replication, which can be rescued by the expression of H3K9M, a histone H3 mutant transgene that reverses the effect of Kdm4d on H3K9 methylation. Kdm4d interacts with replication proteins, and its recruitment to DNA replication origins depends on the two pre-replicative complex components (origin recognition complex [ORC] and minichromosome maintenance [MCM] complex). Depletion of Kdm4d impairs the recruitment of Cdc45, proliferating cell nuclear antigen (PCNA), and polymerase δ, but not ORC and MCM proteins. These results demonstrate a novel mechanism by which Kdm4d regulates DNA replication by reducing the H3K9me3 level to facilitate formation of pre-initiative complex.

Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis

“…Recent studies have shown that the chromatin context in which replication stress occurs can strongly influence DNA damage responses, with the preferential enrichment of γH2AX in heterochromatic regions marked by H3K9me3 31 , 38 , 39 . Furthermore, the modulation of chromatin structure and specifically H3K9me3 is able to modify DNA replication, restore repair capacity and suppress DNA damage 38 – 40 . We, therefore, ascertained the chromatin localisation of DNA damage observed following MMC in Vhl −/− MEFs and found that γH2AX foci were preferentially associated with H3K9me3-marked chromatin (Fig.…”

“…Our data shows that in the case of ccRCC, rescue of the replication stress response can be achieved through loss of the SWI/SNF chromatin remodeller PBRM1 and appears to be mediated, at least in part, through changes in H3K9me3-marked heterochromatin. H3K9me3 has been previously shown to play a critical role in linking chromatin structure to replication and the DDR response 31 , 40 , 47 . Furthermore, modulation of H3K9me3 can rescue the DNA repair defects observed with ATM deficiency 38 as well as the damage accumulation and early senescence associated with progeria 39 .…”

Multi-dimensional histone methylations for coordinated regulation of gene expression under hypoxia

“…Recently, Wu et al. proposed a novel function of JMJD2D to facilitate DNA replication by reducing H3K9me3 ( 66 ), suggesting that hypoxic increase of H3K9me3 can influence DNA replication. Histone demethylases that play important roles in association with gene expression as well as with DNA replication can contribute to pathogenesis of hypoxia-related disease ( 67 , 68 ).…”

Polo-like kinase 1 (PLK1)-dependent phosphorylation of methylenetetrahydrofolate reductase (MTHFR) regulates replication via histone methylation

“…19 Intriguingly, KDM4D, the H3K9me3 demethylase, is recruited to replication origins by ORC and MCM complexes, which further enlist Cdc45, PCNA and polymerases. 43 It was postulated that H3K9me3 levels were attenuated by Kdm4d to facilitate formation of the pre-initiation complex. Concomitantly, SUMOylation of ORC2 is also involved in recruiting KDM5A, the demethylase to convert H3K4me3 to H3K4me2, the ablation of which caused re-replication of the heterochromatin.…”