Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9

Wu, Hong; Mathioudakis, N.; Diagouraga, Boubou; Dong, Aiping; Dombrovski, L.; Baudat, Frédéric; Cusack, Stephen; Massy, Bernard de; Kadlec, Jan

doi:10.1016/j.celrep.2013.08.035

Cited by 116 publications

(132 citation statements)

References 31 publications

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“…H3K36me3 is specifically enriched at recombination sites in a Spo11-independent manner PRDM9 catalyzes H3K36me3 formation in vitro (Wu et al 2013;Eram et al 2014), and H3K36me3 enrichment is detected in vivo at the center of mouse hotspots (Davies et al 2016;Powers et al 2016). Interestingly, we only detected this PRDM9-dependent H3K36me3 enrichment in class 1 PRDM9 binding sites and not in classes 2A or 2B (Fig.…”

Section: Prdm9 Binding Sites Without Recombination Activitymentioning

confidence: 60%

“…Different from S. cerevisiae, these hotspots are not preferentially located in promoter regions, but they are enriched in H3K4me3 (Buard et al 2009;Smagulova et al 2011), presumably through PRDM9 methyltransferase activity (Hayashi et al 2005). Indeed, PRDM9 can methylate histone H3 at K4, K9, and K36 in vitro (Wu et al 2013;Eram et al 2014;Koh-Stenta et al 2014). Like H3K4me3, H3K36me3 also can be associated with nucleosomes adjacent to hotspots (Buard et al 2009;Davies et al 2016;Powers et al 2016).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 96%

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In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

et al. 2017

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In mouse and human meiosis, DNA double-strand breaks (DSBs) initiate homologous recombination and occur at specific sites called hotspots. The localization of these sites is determined by the sequence-specific DNA binding domain of the PRDM9 histone methyl transferase. Here, we performed an extensive analysis of PRDM9 binding in mouse spermatocytes. Unexpectedly, we identified a noncanonical recruitment of PRDM9 to sites that lack recombination activity and the PRDM9 binding consensus motif. These sites include gene promoters, where PRDM9 is recruited in a DSB-dependent manner. Another subset reveals DSB-independent interactions between PRDM9 and genomic sites, such as the binding sites for the insulator protein CTCF. We propose that these DSB-independent sites result from interactions between hotspot-bound PRDM9 and genomic sequences located on the chromosome axis.

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Section: Prdm9 Binding Sites Without Recombination Activitymentioning

confidence: 60%

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 96%

In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

et al. 2017

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“…There have been reports of histone methylation activity by several PRDM proteins in addition to PRDM9 (Derunes et al 2005; Eom et al 2009; Pinheiro et al 2012); however, structural studies have suggested that these PR/SET domains lack residues necessary for binding to S -adenosyl methionine (Wu et al 2013), the cofactor that donates methyl groups for KMT activity. Extensive research by several groups, including our own, has failed to establish enzymatic activity for these enzymes.…”

Section: Molecular Mechanisms Of Set Domain Nonhistone Methylation Inmentioning

confidence: 99%

Nonhistone Lysine Methylation in the Regulation of Cancer Pathways

Carlson

Gozani

2016

Cold Spring Harb Perspect Med

104

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Proteins are regulated by an incredible array of posttranslational modifications (PTMs). Methylation of lysine residues on histone proteins is a PTM with well-established roles in regulating chromatin and epigenetic processes. The recent discovery that hundreds and likely thousands of nonhistone proteins are also methylated at lysine has opened a tremendous new area of research. Major cellular pathways involved in cancer, such as growth signaling and the DNA damage response, are regulated by lysine methylation. Although the field has developed quickly in recent years many fundamental questions remain to be addressed. We review the history and molecular functions of lysine methylation. We then discuss the enzymes that catalyze methylation of lysine residues, the enzymes that remove lysine methylation, and the cancer pathways known tobe regulated by lysine methylation. The rest of the article focuses on two open questions that we suggest as a roadmap for future research. First is understanding the large number of candidate methyltransferase and demethylation enzymes whose enzymatic activity is not yet defined and which are potentially associated with cancer through genetic studies. Second is investigating the biological processes and cancer mechanisms potentially regulated by the multitude of lysine methylation sites that have been recently discovered.

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“…PRDM9 comprises an N-terminal Krüppel-associated box (KRAB) domain; a central PR-SET domain, known for catalyzing histone H3 Lys4 (H3K4) trimethylation (Hayashi et al 2005;Wu et al 2013;Eram et al 2014;Koh-Stenta et al 2014); and a C-terminal tandem array of multiple Cys2-His2 (C2H2) zinc fingers (ZnFs) (Fig. 1A;Supplemental Fig.…”

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confidence: 99%

Structural basis for human PRDM9 action at recombination hot spots

et al. 2016

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The multidomain zinc finger (ZnF) protein PRDM9 (PRD1-BF1-RIZ1 homologous domain-containing 9) is thought to influence the locations of recombination hot spots during meiosis by sequence-specific DNA binding and trimethylation of histone H3 Lys4. The most common variant of human PRDM9, allele A (hPRDM9 A ), recognizes the consensus sequence 5 ′ -NCCNCCNTNNCCNCN-3 ′ . We cocrystallized ZnF8-12 of hPRDM9 A with an oligonucleotide representing a known hot spot sequence and report the structure here. ZnF12 was not visible, but ZnF8-11, like other ZnF arrays, follows the right-handed twist of the DNA, with the α helices occupying the major groove. Each α helix makes hydrogen-bond (H-bond) contacts with up to four adjacent bases, most of which are purines of the complementary DNA strand. The consensus C:G base pairs H-bond with conserved His or Arg residues in ZnF8, ZnF9, and ZnF11, and the consensus T:A base pair H-bonds with an Asn that replaces His in ZnF10. Most of the variable base pairs (N) also engage in H bonds with the protein. These interactions appear to compensate to some extent for changes from the consensus sequence, implying an adaptability of PRDM9 to sequence variations. We investigated the binding of various alleles of hPRDM9 to different hot spot sequences. Allele C was found to bind a C-specific hot spot with higher affinity than allele A bound A-specific hot spots, perhaps explaining why the former is dominant in A/C heterozygotes. Allele L13 displayed higher affinity for several A-specific sequences, allele L9/L24 displayed lower affinity, and allele L20 displayed an altered sequence preference. These differences can be rationalized structurally and might contribute to the variation observed in the locations and activities of meiotic recombination hot spots.

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Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9

Cited by 116 publications

References 31 publications

In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

Nonhistone Lysine Methylation in the Regulation of Cancer Pathways

Structural basis for human PRDM9 action at recombination hot spots

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