Specificity of MLL1 and TET3 CXXC domains towards naturally occurring cytosine modifications

Stroynowska-Czerwinska, Anna; Piasecka, Anna; Bochtler, Matthias

doi:10.1016/j.bbagrm.2018.10.009

Cited by 4 publications

(6 citation statements)

References 29 publications

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“…All these results indicated that the formation of the native complex has been captured in atomic resolution. These results also agreed with experimental observations that the MLL1‐CXXC domain especially recognizes unmethylated CpG site 8,9,45 …”

Section: Resultssupporting

confidence: 91%

“…CXXC domain can participate in the methylation process of DNA by recognizing unmethylated CpG sites as observed in MLL, DNMT1, and CFP1. CXXC domain can also regulate the demethylation of DNA by specifically binding to methyl‐, formyl‐, and carboxyl modified CpG sites as demonstrated by proteins like TETs 45 . It is also interesting to note that all known CXXC domains share similar sequences and structures.…”

Section: Discussionmentioning

confidence: 96%

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C1188D mutation abolishes specific recognition between MLL1‐CXXC domain and CpG site by inducing conformational switch of flexible N‐terminal

Chen

Duan

et al. 2020

Proteins

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Mixed lineage leukemia protein (MLL1 protein) recognizes the CpG site via its CXXC domain and is frequently associated with leukemia. The specific recognition is abolished by C1188D mutation, which also prevents MLL-related leukemia. In this paper, multiple molecular dynamic (MD) simulations were performed to investigate the mechanism of recognition and influences of C1188D mutation. Started from fully dissociated DNA and MLL1-CXXC domain, remarkably, the center of mass (COM) of MLL1-CXXC domain quickly concentrates on the vicinity of the CpG site in all 53 short MD simulations. Extended simulations of the wild type showed that the native complex formed in 500 ns among 4 of 53 simulations. In contrast, the C1188D mutant COM distributed broadly around the DNA and the native complex was not observed in any of the extended simulations. Simulations on the apo MLL1-CXXC domain further suggest that the wild type protein remained predominantly in an open form that closely resembles its structure in the native complex whereas C1188D mutant formed predominantly compact structures in which the Nterminal bends to D1188. This conformational switch hinders the formation of encounter complex, thus abolishes the recognition. Our study also provides clues to the study mechanism of recognition, by the CXXC domain from proteins like DNA methyltransferase and ten-eleven translocation enzymes.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 96%

C1188D mutation abolishes specific recognition between MLL1‐CXXC domain and CpG site by inducing conformational switch of flexible N‐terminal

Chen

Duan

et al. 2020

Proteins

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“…Currently, there is no evidence that the bromodomains could contribute to the preference of KMT2A-B for promoters over enhancers. By contrast, KMT2A CXXC domains bind only at unmodified CpGs and are repelled by any single cytosine modification [ 12 , 23 ]. Unmodified CpGs are enriched in CpG islands (CGIs) mostly within active promoters, but not elsewhere in the genome [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers

Stroynowska-Czerwinska

Klimczak

Pastor

et al. 2023

Cell. Mol. Life Sci.

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Histone lysine-specific methyltransferase 2 (KMT2A-D) proteins, alternatively called mixed lineage leukemia (MLL1-4) proteins, mediate positive transcriptional memory. Acting as the catalytic subunits of human COMPASS-like complexes, KMT2A-D methylate H3K4 at promoters and enhancers. KMT2A-D contain understudied highly conserved triplets and a quartet of plant homeodomains (PHDs). Here, we show that all clustered (multiple) PHDs localize to the well-defined loci of H3K4me3 and H3 acetylation-rich active promoters and enhancers. Surprisingly, we observe little difference in binding pattern between PHDs from promoter-specific KMT2A-B and enhancer-specific KMT2C-D. Fusion of the KMT2A CXXC domain to the PHDs drastically enhances their preference for promoters over enhancers. Hence, the presence of CXXC domains in KMT2A-B, but not KMT2C-D, may explain the promoter/enhancer preferences of the full-length proteins. Importantly, targets of PHDs overlap with KMT2A targets and are enriched in genes involved in the cancer pathways. We also observe that PHDs of KMT2A-D are mutated in cancer, especially within conserved folding motifs (Cys4HisCys2Cys/His). The mutations cause a domain loss-of-function. Taken together, our data suggest that PHDs of KMT2A-D guide the full-length proteins to active promoters and enhancers, and thus play a role in positive transcriptional memory. Graphical Abstract

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“…PTIP, a component of COMPASS-like complexes with KMT2C/D catalytic core recruits them to Pax proteins (Lechner et al, 2000). Moreover, only promoter-specific KMT2A-B contain CXXC domains, which localize the proteins to non-modified CpGs and single modification of CpG was shown to abolish this interaction (Cierpicki et al, 2010;Stroynowska-Czerwinska et al, 2018). These CpGs are enriched in CpG islands (CGIs) of active promoters, but not elsewhere in the genome (Bird, 1986).…”

Section: Multiple Mechanisms Contribute To the Targeting Of Kmt2a-dmentioning

confidence: 99%

“…1a). Only promoterspecific KMT2A and KMT2B possess CXXC domains which bind non-modified CpGs [21][22][23], the hallmark of active promoters [24]. Furthermore, all KMT2A-D proteins contain several chromatin readers, the PHD domains (PHDs).…”

Section: Introductionmentioning

confidence: 99%

Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers

Stroynowska-Czerwinska

Klimczak

Pastor

et al. 2021

Preprint

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Histone lysine methyltransferase (KMT2) proteins form the core of COMPASS and COMPASS-like complexes that mediate transcriptional memory by methylating H3K4 at promoters and enhancers. KMT2A-D proteins, alternatively called mixed lineage leukaemia proteins (MLL1-4), contain highly conserved unique triplet and quartet of plant homeodomains (PHDs). Here, we show that clustered PHDs, expressed in isolation in HeLa cells, localize to well-defined loci of acetylation-rich active promoters and enhancers. Binding sites overlap with targets of full-length KMT2A (MLL1) and the COMPASS-like subunit WDR5, RbBP5 and with cell cycle and cancer-related genes. COSMIC data identify frequent variations in the PHDs of KMT2 proteins, particularly KMT2C, in a wide spectrum of malignancies. Changes are enriched at conserved positions within the PHDs, indicating that they cause loss-of-function mutations. Taken together, the biochemical and cancer data suggest that the PHDs contribute to KMT2A-D targeting to active promoters and enhancers.

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Specificity of MLL1 and TET3 CXXC domains towards naturally occurring cytosine modifications

Cited by 4 publications

References 29 publications

C1188D mutation abolishes specific recognition between MLL1‐CXXC domain and CpG site by inducing conformational switch of flexible N‐terminal

C1188D mutation abolishes specific recognition between MLL1‐CXXC domain and CpG site by inducing conformational switch of flexible N‐terminal

Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers

Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers

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