Mind the Methyl: Methyllysine Binding Proteins in Epigenetic Regulation

Wagner, Tobias; Robaa, Dina; Sippl, Wolfgang; Jung, Manfred

doi:10.1002/cmdc.201300422

Cited by 39 publications

(42 citation statements)

References 184 publications

(399 reference statements)

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“…These reader proteins are involved in the pathogenesis of various diseases and identifying small molecules that inhibit interactions between histone methyl-lysine readers and their respective binding partners on chromatin has significant clinical relevance 41 . Here with TIRR, we have the first example of a bona fide cellular inhibitor of a histone methyl-lysine reader.…”

Section: Discussionmentioning

confidence: 99%

TIRR regulates 53BP1 by masking its histone methyl-lysine binding function

Drané¹,

Brault²,

Cui³

et al. 2017

Nature

126

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SUMMARY53BP1 is a multi-functional double-strand break (DSB) repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumors to PARP inhibitors. Central to all 53BP1 activities is its recruitment to DSBs via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, TIRR (Tudor Interacting Repair Regulator) that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, ATM phosphorylates 53BP1 and recruits RIF1 to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to DSBs. Depletion of TIRR destabilizes 53BP1 in the nuclear soluble fraction and also alters the DSB-induced protein complex centering 53BP1. These findings identify TIRR as a new factor that influences DSB †

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Section: Discussionmentioning

confidence: 99%

TIRR regulates 53BP1 by masking its histone methyl-lysine binding function

Drané¹,

Brault²,

Cui³

et al. 2017

Nature

126

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“…Inhibitors of reader domains are prominently exemplified by JQ1 or I-BET, compounds potently disrupting the interaction of BET bromo domains with acetylated lysine residues [38, 39]. Furthermore, successful targeting of a methyl lysine reader (L3MBTL3A) with the small molecule inhibitor UNC1215 has been reported [40] and several other methyl lysine readers are potential drug targets [41]. Since the F141A mutation in tudor-like domain 2, which blocks SPIN1 chromatin binding, interferes with SPIN1-controlled liposarcoma cell proliferation and survival, targeting the SPIN1/H3K4me3 pocket with small molecule inhibitors might be an interesting alternative therapeutic option for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

The histone code reader SPIN1 controls RET signaling in liposarcoma

et al. 2015

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The histone code reader Spindlin1 (SPIN1) has been implicated in tumorigenesis and tumor growth, but the underlying molecular mechanisms remain poorly understood. Here, we show that reducing SPIN1 levels strongly impairs proliferation and increases apoptosis of liposarcoma cells in vitro and in xenograft mouse models. Combining signaling pathway, genome-wide chromatin binding, and transcriptome analyses, we found that SPIN1 directly enhances expression of GDNF, an activator of the RET signaling pathway, in cooperation with the transcription factor MAZ. Accordingly, knockdown of SPIN1 or MAZ results in reduced levels of GDNF and activated RET explaining diminished liposarcoma cell proliferation and survival. In line with these observations, levels of SPIN1, GDNF, activated RET, and MAZ are increased in human liposarcoma compared to normal adipose tissue or lipoma. Importantly, a mutation of SPIN1 within the reader domain interfering with chromatin binding reduces liposarcoma cell proliferation and survival. Together, our data describe a molecular mechanism for SPIN1 function in liposarcoma and suggest that targeting SPIN1 chromatin association with small molecule inhibitors may represent a novel therapeutic strategy.

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“…In this way, MYC would be recruited to its target genes through a bivalent set of interactions, recognizing both DNA (E-box) and specific protein determinants (chromatin reader bound to a methylated histone tail). A growing number of methyllysine binding proteins have been identified [120] that encompass a structurally diverse set of protein domains and binding mechanisms, making it difficult to predict which if any methyllysine readers may conspire with MYC to direct its binding specificity in vivo. But if such proteins can be found, targeting either their histone binding pockets, or the surfaces through which they interact with MYC, could provide fertile territory for development of anti-MYC therapies in the future.…”

Section: The Impact Of Chromatin On Myc Activitymentioning

confidence: 99%

MYC and Chromatin

Thomas¹,

Tansey

2015

The Open Access Journal of Science and Technology

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Abstract. MYC proteins are a family of oncogene-encoded transcriptional regulators that feature prominently in cancer. They are aberrantly expressed in a majority of human malignancies, and derive their extraordinary oncogenic potential from the ability to control expression of genes linked to cell growth, proliferation, metabolism, and genomic instability. MYC proteins are also highly-validated targets for anti-cancer therapies. Over 30 years of research into MYC has revealed the importance of chromatin in regulating both the production of MYC proteins and their ability to recognize target genes and to function as modulators of transcription. Here, we review contemporary understanding of the MYC-chromatin connection, focusing on how the encasement of DNA into chromatin impacts expression of MYC genes, and how MYC responds to and modulates chromatin to exert its transcriptional effects. We also describe ways in which chromatin structure and function are being manipulated by drug-like molecules to inhibit MYC-driven cancers.

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Mind the Methyl: Methyllysine Binding Proteins in Epigenetic Regulation

Cited by 39 publications

References 184 publications

TIRR regulates 53BP1 by masking its histone methyl-lysine binding function

TIRR regulates 53BP1 by masking its histone methyl-lysine binding function

The histone code reader SPIN1 controls RET signaling in liposarcoma

MYC and Chromatin

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