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Histone Demethylation and Timely DNA Replication Molecular Cell Previews Histone Demethylation and Timely DNA Replication Erica L. Gerace1 and Danesh Moazed1,2,* 1Department of Cell Biology 2Howard Hughes Medical Institute Harvard Medical School, Boston, MA 02115, USA *Correspondence: [email protected] DOI 10.1016/j.molcel.2010.11.036 It is well-established that silent regions of the genome replicate late during S phase. In this issue of Molecular Cell, Black et al. (2010) uncover a conserved role for the JMJD2 family of histone demethylases in promoting replication within silent chromatin regions that contain histone H3 lysine 9 methylation and HP1. The faithful replication of the genome JMJD2 family was found to catalyze the level of initiation and/or fork during each cell division is a vital process the demethylation of trimethylated H3K9, progression. that is highly coordinated and tightly H3K36, and H1.4K26 (Fodor et al., 2006; Analysis of jmjd-2À/À worms revealed controlled. In eukaryotic cells, origins of Klose et al., 2006; Trojer et al., 2009; a decreased number of cells within the DNA replication, the sites where replica- Whetstine et al., 2006). Depletion of mitotic zone and an increased number of tion begins, are found throughout the JMJD-2 in C. elegans results in the activa- RAD-51 foci, an indication of stalled or genome and fire at different times tion of a DNA damage-induced apoptosis collapsed replication forks. Furthermore, throughout S phase. This timing is influ- (Whetstine et al., 2006), but the molecular direct in vivo visualization of DNA replica- enced by local chromatin structure and basis of this event had not been tion using pulse-chase labeling experi- correlates with cell type-specific differ- established. ments with cy3-dUTP/ALEXA-488-dUTP ences in gene expression and chromatin In this issue of Molecular Cell, Black in the adult germlines of jmjd-2À/À worms structure. Although there are exceptions, et al. (2010) describe a role for histone showed that replication was slowed, sug- in general, transcriptionally active por- demethylation in cell cycle progression gesting that in vivo, JMJD-2 likely affects tions of the genome are replicated earlier and DNA replication. They report that the replication timing. This observation also in S phase than those found in silent, expression of JMJD2A is cell cycle regu- explains the previously observed in- heterochromatic regions (MacAlpine and lated with peak expression at the G1/S creased apoptosis in jmjd-2 mutants Bell, 2005). Histone H3 lysine 9 (H3K9) transition dropping off in S phase and (Whetstine et al., 2006), a phenotype that methylation is a conserved modification lowest at G2/M. The overexpression of Black et al. (2010) also show can be that is found in heterochromatin from JMJD2A, but not catalytically inactive rescued by knockdown of the p53 and fission yeast to human, and defines a JMJD2A, which has a mutation at a key ATR homologs, CEP-1 and ATL-1, re- binding site for Heterochromatin Protein metal-coordinating residue required for spectively. However, the mutation of the 1 (HP1) family members, which help demethylase activity (Whetstine et al., ATM homolog did not provide a rescue make heterochromatin inaccessible. Re- 2006), in human cell lines led to faster of the observed phenotype, indicating cent studies suggest that heterochro- progression through S phase. In addition, that the increased apoptosis is mediated matin is more dynamic than previously the overexpression of JMJD2A resulted through the ATR pathway, which is acti- appreciated and can be broached by in both the early replication of a late- vated after replication stress, but not the machineries that transcribe and repair replicating satellite region, sat2 of chro- ATM pathway, which is typically activated DNA (Kwon and Workman, 2008). How- mosome 1 (Chr1 sat2), as well as faster in response to double-strand breaks. ever, how access to heterochromatin or recovery of these cells after treatment How does JMJD2A-mediated histone other silent regions is regulated is poorly with hydroxyurea (HU), which causes demethylation contribute to DNA rep- understood. replication stress. Similarly, mutating or lication timing? The overexpression of The discovery of histone lysine deme- knocking down the gene for the worm JMJD2A causes the redistribution of thylases suggested new mechanisms for homolog, jmjd-2, resulted in increased HP1 proteins (Klose et al., 2006) likely by regulation of chromatin structure and, sensitivity to HU. These results suggest removing the chromatin mark to which indeed, these enzymes have already that expression of JMJD2A/JMJD-2 dur- HP1 proteins bind, trimethylated H3K9. been identified with numerous roles in ing S phase facilitates DNA replication. So, potentially JMJD2A may regulate regulation of transcription. Histone lysine Consistently, Black et al. also demon- chromatin structure and replication timing demethylation is catalyzed by two distinct strated that more single-stranded DNA via effects on HP1 localization. Indeed, classes of evolutionarily conserved en- was observed during S phase in cells using micrococcal nuclease digestions zymes (Shi and Whetstine, 2007). JmjC ectopically expressing JMJD2A, which of isolated nuclei, Black et al. (2010) domain proteins are metalloenzymes suggests increased presence of replica- observed increased DNA accessibility in that catalyze oxidative reactions. Several tion forks. However, it remains unknown cells overexpressing catalytically active years ago, a JmjC domain protein of the whether the faster S phase effects are at JMJD2A, specifically during S phase. In Molecular Cell 40, December 10, 2010 ª2010 Elsevier Inc. 683 Molecular Cell Previews addition, in these cells, the (1) wild-type regions and the mating type chromatin structure of the locus (Hayashi et al., 2009). late-replicating locus Chr1 JMJD2A Surprisingly, Black et al. sat2 was found to be more HP1γ HP1γ (2010) found that deletion of open corresponding to its H3K9me3 the worm HP1g homolog observed earlier replication. (HPL-2) had the same de- These data support the no- ori layed replication phenotypes tion that altering chromatin as jmjd-2À/À cells, suggesting accessibility can regulate (2) JMJD-2 depletion that intricacies in the balance cell cycle progression and between the two worm HP1 replication timing, providing proteins are also important another way to regulate cell for proper replication timing. HP1γ HP1γ HP1γ cycle that is independent or We can therefore look for- Me Me Me Me Me complimented by altered ward to future studies that transcriptional programs. ori ori will explore possible direct Interestingly, it appears that links between different HP1 JMJD2A/JMJD-2 act by proteins and activation or antagonizing a specific HP1 silencing of DNA replication. isoform. Most cells contain (3) JMJD2A overexpression two or more HP1 homologs, HP1a,-b, and HP1g in human, JMJD2A HP1γ REFERENCES JMJD2A and HPL-1 and -2 in worms. HP1γ Black, J.C., Allen, A., Capucine, The overexpression of HP1g, Me V.R., Forbes, E., Longworth, M., but not HP1a or HP1b, sup- Tscho¨ p, K., Rinehart, C., Quiton, pressed the JMJD2A-depen- ori J., Walsh, R., Smallwood, A., et al. (2010). Mol. Cell 40, this issue, dent increased number of 736–748. cells in late S phase, an effect that depended on Figure 1. Human and C. elegans JMJD2A/JMJD-2 Antagonize Fodor, B.D., Kubicek, S., HP1g/HPL-2 and Promote DNAReplication Yonezawa, M., O’Sullivan, R.J., both the chromodomain and (1) HP1g binds trimethylated histone H3 lysine 9 (H3K9me3), maintaining Sengupta, R., Perez-Burgos, L., chromoshadow domain of a closed chromatin structure, which inhibits the firing of origins of replication Opravil, S., Mechtler, K., Schotta, HP1g. Also, at the Chr1 sat2 or slows the progress of replication forks. Demethylation of H3K9me3 results G., and Jenuwein, T. (2006). Genes in dissociation of HP1g, thus promoting DNA replication and cell cycle Dev. 20, 1557–1562. locus, the overexpression of progression. (2) In JMJD-2-depleted germline nuclei in C. elegans, H3K9me3 JMJD2A decreased HP1g levels and HPL-2/HP1g association increase, leading to delayed replication Hayashi, M.T., Takahashi, T.S., origin firing. Potential spreading of HPL-2/HP1g may also prevent the firing Nakagawa, T., Nakayama, J., and localization. In worms, the Masukata, H. (2009). Nat. Cell Biol. À/À of distally located origins of replication. (3) During S phase or when JMJD2A jmjd-2 phenotypes of in- 11, 357–362. is overexpressed, demethylation of H3K9me3 and HP1g displacement allow creased RAD-51 foci, de- origin firing resulting in faster progression through S phase. Klose, R.J., Yamane, K., Bae, Y., creased number of nuclei in Zhang, D., Erdjument-Bromage, the mitotic zone, slowed replication, and at specific heterochromatic regions, anal- H., Tempst, P., Wong, J., and Zhang, Y. (2006). increased apoptosis are all rescued by ogous to human satellite repeats. The Nature 442, 312–316. the depletion of HP1 homolog HPL-2, findings also add to an emerging body of Kwon, S.H., and Workman, J.L. (2008). Mol. Cells establishing a conserved antagonistic evidence that suggests distinct roles for 26, 217–227. relationship between these two proteins. different HP1 proteins in regulation of MacAlpine, D.M., and Bell, S.P. (2005). Chromo- Together the results suggest that DNA replication and other heterochro- some Res. 13, 309–326. JMJD2A/JMJD-2 modulate replication matin functions, which may relate to Motamedi, M.R., Hong, E.J., Li, X., Gerber, S., timing by opposing reduced DNA acces- protein interactions and/or genomic loca- Denison, C., Gygi, S., and Moazed, D. (2008). sibility to the replication machinery in tion. For example, the two fission yeast Mol. Cell 32, 778–790. DNA domains that are decorated by homologs, Swi6 and Chp2, play distinct Shi,Y., and Whetstine, J.R. (2007). Mol.Cell25,1–14. H3K9 trimethylation and HP1g (Figure 1). roles in replication of heterochromatin It remains to be determined whether the and gene silencing (Hayashi et al., 2009; Trojer, P., Zhang, J., Yonezawa, M., Schmidt, A., HP1 Zheng, H., Jenuwein, T., and Reinberg, D.
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