The global inhibition of transcription at the mitotic phase of the cell cycle occurs together with the general displacement of transcription factors from the mitotic chromatin. Nevertheless, the DNase-and potassium permanganate-hypersensitive sites are maintained on potentially active promoters during mitosis, helping to mark active genes at this stage of the cell cycle. Our study focuses on the role of histone acetylation and H3 (Lys-4) methylation in the maintenance of the competency of these active genes during mitosis. To this end we have analyzed histone modifications across the promoters and coding regions of constitutively active, inducible, and inactive genes in mitotic arrested cells. Our results show that basal histone modifications are maintained during mitosis at promoters and coding regions of the active and inducible RNA polymerase II-transcribed genes. In addition we have demonstrated that, together with H3 acetylation and H3 (Lys-4) methylation, H4 (Lys-12) acetylation at the coding regions contributes to the formation of a stable mark on active genes at this stage of the cell cycle. Finally, analysis of cyclin B1 gene activation during mitosis revealed that the former occurs with a strong increase of H3 (Lys-4) trimethylation but not H3 or H4 acetylation, suggesting that histone methyltransferases are active during this stage. These data demonstrate a critical role of histone acetylation and H3 (Lys-4) methylation during mitosis in marking and activating genes during the mitotic stage of the cell cycle.
SummaryThe existence of different patterns of chemical modifications (acetylation, methylation, phosphorylation, ubiquitination and ADP-ribosylation) of the histone tails led, some years ago, to the histone code hypothesis. According to this hypothesis, these modifications would provide binding sites for proteins that can change the chromatin state to either active or repressed. Interestingly, some protein domains present in histone-modifying enzymes are known to interact with these covalent marks in the histone tails. This was first shown for the bromodomain, which was found to interact selectively with acetylated lysines at the histone tails. More recently, it has been described that the chromodomain can be targeted to methylation marks in histone N-terminal domains. Finally, the interaction between the SANT domain and histones is also well documented. Overall, experimental evidence suggests that these domains could be involved in the recruitment of histone-modifying enzymes to discrete chromosomal locations, and/or in the regulation their enzymatic activity. Within this context, we review the distribution of bromodomains, chromodomains and SANT domains among chromatin-modifying enzymes and discuss how they can contribute to the translation of the histone code. The histone code hypothesis The packing of the eukaryotic genome into chromatin provides the means for compaction of the entire genome inside the nucleus. However, this packing restricts the access to DNA of the many regulatory proteins essential for biological processes like replication, transcription, DNA repair and recombination.(1)There are two mechanisms that can counterbalance the repressive nature of chromatin, allowing access to nucleosomal DNA: (i) covalent modification of histone tails like acetylation, methylation, phosphorylation and ubiquitination; (2)(3)(4)(5) and (ii) altering of the nucleosomal structure by enzymes utilising energy from ATP hydrolysis.In the early nineties, it was proposed that histone covalent modifications can work as recognition signals, directing the binding to chromatin of non-histone proteins that determine chromatin function. (7,8) More recently, it has been hypothesized that specific tail modifications and/or their combinations constitute a code, the histone code, that determines the transcriptional state of the genes. (9)(10)(11) According to this hypothesis, ''multiple histone modifications, acting in a combinatorial or sequential fashion on one or multiple tails, specify unique downstream functions''.In the last years, an increasing amount of experimental data has provided clear support for the different aspects of the histone code hypothesis, contributing to refine and improve it.(For review 12,13) One important point that has been addressed by different authors is the idea that the histone code must use combinations of modifications.(9) For example, H3 methylated at K9 could initiate chromatin condensation and silencing (14,15) but, in the context of methylated H3K4 and H4K20, methyl-K9 H3 helps to maintain ...
Active chromatin remodelling is integral to the DNA damage response in eukaryotes, as damage sensors, signalling molecules and repair enzymes gain access to lesions. A variety of nucleosome remodelling complexes is known to promote different stages of DNA repair. The nucleosome sliding factors CHRAC/ACF of Drosophila are involved in chromatin organization during development. Involvement of corresponding hACF1-containing mammalian nucleosome sliding factors in replication, transcription and very recently also non-homologous end-joining of DNA breaks have been suggested. We now found that hACF1-containing factors are more generally involved in the DNA damage response. hACF1 depletion increases apoptosis, sensitivity to radiation and compromises the G2/M arrest that is activated in response to UV- and X-rays. In the absence of hACF1, γH2AX and CHK2ph signals are diminished. hACF1 and its ATPase partner SNF2H rapidly accumulate at sites of laser-induced DNA damage. hACF1 is also required for a tight checkpoint that is induced upon replication fork collapse. ACF1-depleted cells that are challenged with aphidicolin enter mitosis despite persistence of lesions and accumulate breaks in metaphase chromosomes. hACF1-containing remodellers emerge as global facilitators of the cellular response to a variety of different types of DNA damage.
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