Structural and functional analyses of methyl‐lysine binding by the malignant brain tumour repeat protein Sex comb on midleg

Grimm, Clemens; Alonso, Andrés Gaytán de Ayala; Rybin, Vladimir; Steuerwald, Ulrich; Ly‐Hartig, Nga; Fischle, Wolfgang; Müller, Jürg; Müller, Christoph

doi:10.1038/sj.embor.7401085

Cited by 61 publications

(110 citation statements)

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“…Moreover, most of the recovered lethal L(3)mbt mutations delete or modify the MBT repeats (32), underscoring the relevance of these structures. It is through its MBT repeats that L(3)mbt preferentially binds mono-and dimethylated lysine residues in histones (20,21). The data analyzed here show very little overlap with any particular type of the mono-and dimethylated lysines found in various histones ( Fig.…”

Section: What Are the Necessary And Sufficient Components For L(3)mbtmentioning

confidence: 73%

“…L(3)mbt has intrinsic chromatin binding capabilities, which require the integrity of its second MBT repeat (14)(15)(16). To establish a contributing mode for vertebrate L(3)mbt recruitment, several studies have provided evidence consistent with L(3)mbt preferentially, albeit promiscuously, interacting with most mono-and dimethylated lysine residues of histones, with very low affinity for the non-or trimethylated forms (15,20,21). The available crystal structures provide evidence of how this methylated-lysine histone binding may be mediated and suggest that the arrangement of MBT repeats is required for protein stability, even if only one repeat performs the actual binding (15,16,22).…”

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confidence: 99%

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Chromatin reader L(3)mbt requires the Myb–MuvB/DREAM transcriptional regulatory complex for chromosomal recruitment

Blanchard

Georlette

Antoszewski

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Lethal malignant brain tumors (lmbt) result from the loss of the conserved transcriptional repressor l(3)mbt, in Drosophila melanogaster. Similar mutations in the human homolog L3MBTL1 correlate with some cancers. The protein's C-terminal MBT repeats bind mono and dimethylated histones in vitro, which could influence recruitment of L3MBTL1 to its target sites. The L(3)mbt chromatin targeting mechanism, however, is controversial and several studies suggest insufficiency or a minor role for histone methylation in determining the site specificity for recruitment. We report that L(3)mbt colocalizes with core members of the Myb-MuvB/DREAM (MMB/DREAM) transcriptional regulatory complex genome-wide, and that L(3)mbt-mediated repression requires this complex in salivary glands and larval brains. Loss of l(3)mbt or of MMB components through mutation cause similar spurious expression of genes, including the transposon regulatory gene piwi, in terminally differentiated cells. The DNA-binding MMB core component Mip120 (Lin54) is required for L(3)mbt recruitment to chromosomes, whereas Mip130 (Lin9) (an MMB core protein) and E2f2 (an MMB transcriptional repressor) are not, but are essential for repression. Cytolocalization experiments suggest the presence of sitespecific differential composition of MMB in polytene chromosomes where some loci were bound by a Myb-containing or alternatively, an E2f2 and L(3)mbt form of the complex.epigenetics | bar coding | tumorigenesis

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Section: What Are the Necessary And Sufficient Components For L(3)mbtmentioning

confidence: 73%

mentioning

confidence: 99%

Chromatin reader L(3)mbt requires the Myb–MuvB/DREAM transcriptional regulatory complex for chromosomal recruitment

Blanchard

Georlette

Antoszewski

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…41 In vitro studies using isolated MBT domains and histone peptides have demonstrated a general preference for binding to mono-or di-methylated, over un-or tri-methylated peptides. 27,[42][43][44][45][46][47][48][49] An exception to this general rule is provided by the Caenorhabditis elegans protein LIN-61, which displays specificity toward di-and tri-methylated H3K9 histone peptides. 50 A recent study investigating the MBT domains of all 9 human family members has found that some MBT domains (L3MBTL1, L3MBTL3) recognize mono-and/or di-methyl-lysine in a promiscuous, non-sequence-specific fashion, whereas others (SCML2, L3MBTL4, MBTD1, L3MBTL2) specifically bind to only a few selected histone sequences.…”

Section: -23mentioning

confidence: 99%

Chromatin regulation: How complex does it get?

Meier¹,

Brehm

2014

Epigenetics

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“…In Drosophila, only two further MBT domaincontaining proteins exist, Sex comb on midleg (scm) (6,(22)(23)(24) and Sex comb with four MBT domains (sfmbt) (5,13,14). Both are members of Polycomb group-related complexes (scm: PRC1 (22); sfmbt: PhoRC (14)) and are required for repression of Hox gene expression during development.…”

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confidence: 99%

Chromatin Protein L3MBTL1 Is Dispensable for Development and Tumor Suppression in Mice

Qin

Buren

Huang

et al. 2010

Journal of Biological Chemistry

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L3MBTL1, a paralogue of Drosophila tumor suppressor lethal(3)malignant brain tumor (l(3)mbt), binds histones in a methylation state-dependent manner and contributes to higher order chromatin structure and transcriptional repression. It is the founding member of a family of MBT domain-containing proteins that has three members in Drosophila and nine in mice and humans. Knockdown experiments in cell lines suggested that L3MBTL1 has non-redundant roles in the suppression of oncogene expression. We generated a mutant mouse strain that lacks exons 13-20 of L3mbtl1. Markedly reduced levels of a mutant mRNA with an out-of-frame fusion of exons 12 and 21 were expressed, but a mutant protein was undetectable by Western blot analysis. L3MBTL1 ؊/؊ mice developed and reproduced normally.The highest expression of L3MBTL1 was detected in the brain, but its disruption did not affect brain development, spontaneous movement, and motor coordination. Despite previous implications of L3mbtl1 in the biology of hematopoietic transcriptional regulators, lack of L3MBTL1 did not result in deficiencies in lymphopoiesis or hematopoiesis. In contrast with its demonstrated biochemical activities, embryonic stem (ES) cells lacking L3MBTL1 displayed no abnormalities in H4 lysine 20 (H4K20) mono-, di-, or trimethylation; had normal global chromatin density as assessed by micrococcal nuclease digests; and expressed normal levels of c-myc. Embryonic fibroblasts lacking L3MBTL1 displayed unaltered cell cycle arrest and down-regulation of cyclin E expression after irradiation. In cohorts of mice followed for more than 2 years, lack of L3MBTL1 did not alter normal lifespan or survival with or without sublethal irradiation.Proteins containing malignant brain tumor (MBT) 3 domains have recently attracted considerable attention because of their emerging role in modulating the organization of cellular DNA in aggregated nucleosomes and chromatin and their important roles in development (1-6). Similar to their better known distant relatives, chromo-and tudor domains, these protein modules selectively bind histone tails depending on the degree of methylation at specific lysine residues (7,8). MBT domains are highly conserved from Drosophila to mammals, comprise ϳ100 amino acid residues, and the structure of multiple family members has been resolved at the atomic level (2, 3, 6, 9 -13). Characteristically, MBT domains recognize mono-and dimethylated lysine residues in histone tails but not non-or trimethylated lysines (2-4, 7, 14). Human L3MBTL1, a transcriptional repressor and suspected tumor suppressor gene (15-17), was shown to be capable of compacting nucleosomal arrays by binding mono-and dimethylated histone H4K20 and histone H1bK26 in vitro (4). Thus, MBT domain proteins contribute to the complex organization of chromatin as "readers" and "effectors" of a network of post-translational histone modifications that is critical for the establishment of specific cellular differentiation states (18 -20).MBT domains were first recognized in the cloned gene ...

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Structural and functional analyses of methyl‐lysine binding by the malignant brain tumour repeat protein Sex comb on midleg

Cited by 61 publications

References 18 publications

Chromatin reader L(3)mbt requires the Myb–MuvB/DREAM transcriptional regulatory complex for chromosomal recruitment

Chromatin reader L(3)mbt requires the Myb–MuvB/DREAM transcriptional regulatory complex for chromosomal recruitment

Chromatin regulation: How complex does it get?

Chromatin Protein L3MBTL1 Is Dispensable for Development and Tumor Suppression in Mice

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