Abstract
BackgroundIn eukaryotes, heterochromatin replicates late in S phase of the cell cycle and contains specific covalent modifications of histones. SuUR mutation found in Drosophila makes heterochromatin replicate earlier than in wild type and reduces the level of repressive histone modifications. SUUR protein was shown to be associated with moving replication forks, apparently through the interaction with PCNA. The biological process underlying the effects of SUUR on replication and composition of heterochromatin remains unknown.ResultsHere we performed a functional dissection of SUUR protein effects on H3K27me3 level. Using hidden Markow model-based algorithm we revealed SuUR-sensitive chromosomal regions that demonstrated unusual characteristics: They do not contain Polycomb and require SUUR function to sustain H3K27me3 level. We tested the role of SUUR protein in the mechanisms that could affect H3K27me3 histone levels in these regions. We found that SUUR does not affect the initial H3K27me3 pattern formation in embryogenesis or Polycomb distribution in the chromosomes. We also ruled out the possible effect of SUUR on histone genes expression and its involvement in DSB repair.ConclusionsObtained results support the idea that SUUR protein contributes to the heterochromatin maintenance during the chromosome replication. A model that explains major SUUR-associated phenotypes is proposed.
Highlights
In eukaryotes, heterochromatin replicates late in S phase of the cell cycle and contains specific covalent modifications of histones
Locally elevated polytenization level could result in the decrease in H3K27me3 ChIP/ input signal in Suppressor of Under-replication (SuUR) mutants observed in previous studies [13, 21]
In wild type, H3K27 methylation in these regions could be a response to under-replication and double-stranded DNA breaks [26, 27], which disappear in SuUR mutants [15, 18]
Summary
Heterochromatin replicates late in S phase of the cell cycle and contains specific covalent modifications of histones. Heterochromatic regions complete replication late in S phase when the rest of the chromosome has already been copied [1,2,3]. Heterochromatic state in Drosophila is established by two major repressive pathways: HP1-dependent [6] and Polycomb-dependent [7] These pathways result in the formation of repressed chromosomal domains marked by H3K9me2/3 and H3K27me, respectively. Su(var) protein is responsible for di- and tri-methylation of H3K9 mainly at pericentric regions [8] This mark is recognized by the chromodomain of HP1 protein [9] that, together with other heterochromatic factors, completes the formation of specific chromatin state in pericentric regions. PRC2 places methylation mark on H3K27, and PRC1 binds this mark and causes gene repression [7]
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