Publications

• Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage.

  Sanders S.L., Portoso M., Mata J., Baehler J., Allshire R.C., Kouzarides T.

  Histone lysine methylation is a key regulator of gene expression and heterochromatin function, but little is known as to how this modification impinges on other chromatin activities. Here we demonstrate that a previously uncharacterized SET domain protein, Set9, is responsible for H4-K20 methylati ... >> More

  Histone lysine methylation is a key regulator of gene expression and heterochromatin function, but little is known as to how this modification impinges on other chromatin activities. Here we demonstrate that a previously uncharacterized SET domain protein, Set9, is responsible for H4-K20 methylation in the fission yeast Schizosaccharomyces pombe. Surprisingly, H4-K20 methylation does not have any apparent role in the regulation of gene expression or heterochromatin function. Rather, we find the modification has a role in DNA damage response. Loss of Set9 activity or mutation of H4-K20 markedly impairs cell survival after genotoxic challenge and compromises the ability of cells to maintain checkpoint mediated cell cycle arrest. Genetic experiments link Set9 to Crb2, a homolog of the mammalian checkpoint protein 53BP1, and the enzyme is required for Crb2 localization to sites of DNA damage. These results argue that H4-K20 methylation functions as a "histone mark" required for the recruitment of the checkpoint protein Crb2. << Less

  Cell 119:603-614(2004) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin.

  Schotta G., Lachner M., Sarma K., Ebert A., Sengupta R., Reuter G., Reinberg D., Jenuwein T.

  Histone lysine methylation is a central modification to mark functionally distinct chromatin regions. In particular, H3-K9 trimethylation has emerged as a hallmark of pericentric heterochromatin in mammals. Here we show that H4-K20 trimethylation is also focally enriched at pericentric heterochrom ... >> More

  Histone lysine methylation is a central modification to mark functionally distinct chromatin regions. In particular, H3-K9 trimethylation has emerged as a hallmark of pericentric heterochromatin in mammals. Here we show that H4-K20 trimethylation is also focally enriched at pericentric heterochromatin. Intriguingly, H3-K9 trimethylation by the Suv39h HMTases is required for the induction of H4-K20 trimethylation, although the H4 Lys 20 position is not an intrinsic substrate for these enzymes. By using a candidate approach, we identified Suv4-20h1 and Suv4-20h2 as two novel SET domain HMTases that localize to pericentric heterochromatin and specifically act as nucleosomal H4-K20 trimethylating enzymes. Interaction of the Suv4-20h enzymes with HP1 isoforms suggests a sequential mechanism to establish H3-K9 and H4-K20 trimethylation at pericentric heterochromatin. Heterochromatic H4-K20 trimethylation is evolutionarily conserved, and in Drosophila, the Suv4-20 homolog is a novel PEV modifier to regulate position-effect variegation. Together, our data indicate a function for H4-K20 trimethylation in gene silencing and further suggest H3-K9 and H4-K20 trimethylation as important components of a repressive pathway that can index pericentric heterochromatin. << Less

  Genes Dev. 18:1251-1262(2004) [PubMed] [EuropePMC]

• A novel route to product specificity in the Suv4-20 family of histone H4K20 methyltransferases.

  Southall S.M., Cronin N.B., Wilson J.R.

  The delivery of site-specific post-translational modifications to histones generates an epigenetic regulatory network that directs fundamental DNA-mediated processes and governs key stages in development. Methylation of histone H4 lysine-20 has been implicated in DNA repair, transcriptional silenc ... >> More

  The delivery of site-specific post-translational modifications to histones generates an epigenetic regulatory network that directs fundamental DNA-mediated processes and governs key stages in development. Methylation of histone H4 lysine-20 has been implicated in DNA repair, transcriptional silencing, genomic stability and regulation of replication. We present the structure of the histone H4K20 methyltransferase Suv4-20h2 in complex with its histone H4 peptide substrate and S-adenosyl methionine cofactor. Analysis of the structure reveals that the Suv4-20h2 active site diverges from the canonical SET domain configuration and generates a high degree of both substrate and product specificity. Together with supporting biochemical data comparing Suv4-20h1 and Suv4-20h2, we demonstrate that the Suv4-20 family enzymes take a previously mono-methylated H4K20 substrate and generate an exclusively di-methylated product. We therefore predict that other enzymes are responsible for the tri-methylation of histone H4K20 that marks silenced heterochromatin. << Less

  Nucleic Acids Res. 42:661-671(2014) [PubMed] [EuropePMC]

• Histone H4 lysine 20 methylation: key player in epigenetic regulation of genomic integrity.

  Jorgensen S., Schotta G., Sorensen C.S.

  Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. Nuclear DNA is packaged into chromatin, and thus genome maintenance can be influenced by distinct chromatin environments. In particular, post-translational modifications of ... >> More

  Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. Nuclear DNA is packaged into chromatin, and thus genome maintenance can be influenced by distinct chromatin environments. In particular, post-translational modifications of histones have emerged as key regulators of genomic integrity. Intense research during the past few years has revealed histone H4 lysine 20 methylation (H4K20me) as critically important for the biological processes that ensure genome integrity, such as DNA damage repair, DNA replication and chromatin compaction. The distinct H4K20 methylation states are mediated by SET8/PR-Set7 that catalyses monomethylation of H4K20, whereas SUV4-20H1 and SUV4-20H2 enzymes mediate further H4K20 methylation to H4K20me2 and H4K20me3. Disruption of these H4K20-specific histone methyltransferases leads to genomic instability, demonstrating the important functions of H4K20 methylation in genome maintenance. In this review, we explain molecular mechanisms underlying these defects and discuss novel ideas for furthering our understanding of genome maintenance in higher eukaryotes. << Less

  Nucleic Acids Res 41:2797-2806(2013) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Specificity of the SUV4-20H1 and SUV4-20H2 protein lysine methyltransferases and methylation of novel substrates.

  Weirich S., Kudithipudi S., Jeltsch A.

  The SUV4-20H1 and SUV4-20H2 enzymes methylate histone H4 at K20, and they have overlapping and distinct biological effects. Here, by in vitro methylation studies we confirmed that both the murine SUV4-20H enzymes strongly favor the monomethylated H4K20 peptide substrate. We also show that both enz ... >> More

  The SUV4-20H1 and SUV4-20H2 enzymes methylate histone H4 at K20, and they have overlapping and distinct biological effects. Here, by in vitro methylation studies we confirmed that both the murine SUV4-20H enzymes strongly favor the monomethylated H4K20 peptide substrate. We also show that both enzymes only generate dimethylated H4K20 products. We determined the substrate sequence recognition motif of both enzymes using SPOT peptide arrays showing that SUV4-20H1 recognizes an (RY)-Kme1-(IVLM)-(LFI)-X-D sequence. In contrast, SUV4-20H2 shows less specificity and recognizes an X-Kme1-(IVLMK)-(LVFI)-X-(DEV) sequence, which is partially overlapping with SUV4-20H1 but has relaxed specificity at the -1 and +4 positions (if the target H4K20me1 is positon 0). Based on our data, we identify novel peptide substrates for SUV4-20H1 (K1423 of Zinc finger protein castor homolog 1) and SUV4-20H2 (K1423 of Zinc finger protein castor homolog 1, K215 of Protein Mis18-beta and K308 of Centromere protein U). All these lysine residues were already identified to be methylated in human cells, but the responsible PKMT was not known. In addition, we also tested the activity of SUV4-20H enzymes on ERK1, which was recently reported to be methylated by SUV4-20H1 at K302 and K361. However the sequences surrounding both methylation sites do not fit to the specificity profile of SUV4-20H1 and we could not detect methylation of ERK1 by any of the SUV4-20H enzymes. The possible reasons of this discrepancy and its consequences are discussed. << Less

  J Mol Biol 428:2344-2358(2016) [PubMed] [EuropePMC]

• Crystal structures of the human histone H4K20 methyltransferases SUV420H1 and SUV420H2.

  Wu H., Siarheyeva A., Zeng H., Lam R., Dong A., Wu X.H., Li Y., Schapira M., Vedadi M., Min J.

  SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation. In this study, we present the high-resolution crystal structures of human SUV420H1 and SUV420H2 in complex with SAM, and report the ... >> More

  SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation. In this study, we present the high-resolution crystal structures of human SUV420H1 and SUV420H2 in complex with SAM, and report their substrate specificity. Both methyltransferases have a unique N-terminal domain and Zn-binding post-SET domain, and prefer the monomethylated histone H4K20 as a substrate in vitro. No histone H4K20 trimethylation activity was detected by our radioactivity-based assay for either enzyme, consistent with the presence of a conserved serine residue that forms a hydrogen bond with the target lysine side-chain and limits the methylation level. << Less

  FEBS Lett. 587:3859-3868(2013) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.