Molecular determinants for α-tubulin methylation by SETD2

Kearns, Sarah; Mason, Frank M.; Rathmell, W. Kimryn; Park, In Young; Walker, Cheryl L.; Verhey, Kristen J.; Cianfrocco, Michael A.

doi:10.1016/j.jbc.2021.100898

Cited by 14 publications

(10 citation statements)

References 67 publications

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“…Recent studies indicate that the SRI domain can also regulate SETD2’s activity towards non-histone substrates. The binding of SETD2 to α-tubulin depends on both the acidic unstructured C-terminal tail of α-tubulin as well as on the SRI domain of SETD2 [ 94 , 152 ]. Interestingly, a mutation in the SETD2 SRI domain (R2510H) specifically disrupts the interaction between SETD2 and α-tubulin, but not between SETD2 and RNAPII [ 152 ].…”

Section: Function Of Set2/setd2 and H3k36 Methylationmentioning

confidence: 99%

“…As discussed above, the SRI domain is positively charged at cellular pH and critical positively charged residues facilitate the interaction with the negatively charged RNAPII-pCTD [ 119 ]. It is therefore not surprising that the SRI domain of SETD2 also interacts with α-tubulin through its negatively charged C-terminal tail [ 94 ]. Interestingly, the AWS-SET-postSET region of SETD2 also directly interacts with α-tubulin in an in vitro setting [ 152 ].…”

Section: Function Of Set2/setd2 and H3k36 Methylationmentioning

confidence: 99%

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SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

Molenaar

Leeuwen

2022

Cell. Mol. Life Sci.

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Histone modifying enzymes play critical roles in many key cellular processes and are appealing proteins for targeting by small molecules in disease. However, while the functions of histone modifying enzymes are often linked to epigenetic regulation of the genome, an emerging theme is that these enzymes often also act by non-catalytic and/or non-epigenetic mechanisms. SETD2 (Set2 in yeast) is best known for associating with the transcription machinery and methylating histone H3 on lysine 36 (H3K36) during transcription. This well-characterized molecular function of SETD2 plays a role in fine-tuning transcription, maintaining chromatin integrity, and mRNA processing. Here we give an overview of the various molecular functions and mechanisms of regulation of H3K36 methylation by Set2/SETD2. These fundamental insights are important to understand SETD2’s role in disease, most notably in cancer in which SETD2 is frequently inactivated. SETD2 also methylates non-histone substrates such as α-tubulin which may promote genome stability and contribute to the tumor-suppressor function of SETD2. Thus, to understand its role in disease, it is important to understand and dissect the multiple roles of SETD2 within the cell. In this review we discuss how histone methylation by Set2/SETD2 has led the way in connecting histone modifications in active regions of the genome to chromatin functions and how SETD2 is leading the way to showing that we also have to look beyond histones to truly understand the physiological role of an ‘epigenetic’ writer enzyme in normal cells and in disease.

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Section: Function Of Set2/setd2 and H3k36 Methylationmentioning

confidence: 99%

Section: Function Of Set2/setd2 and H3k36 Methylationmentioning

confidence: 99%

SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

Molenaar

Leeuwen

2022

Cell. Mol. Life Sci.

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“…This association is crucial for SETD2 activity and stability. In addition, the SRI domain of SETD2 is also required for microtubule lysine 40 trimethylation (α-TubK40me3) ( 14 , 15 ) ( Figure 2 ). Molenaar et al.…”

Section: Protein Structure Of Setd2mentioning

confidence: 99%

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

Qian

Wang

et al. 2023

Front. Oncol.

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SET domain-containing 2 (SETD2) is a lysine methyltransferase that catalyzes histone H3 lysine36 trimethylation (H3K36me3) and has been revealed to play important roles in the regulation of transcriptional elongation, RNA splicing, and DNA damage repair. SETD2 mutations have been documented in several cancers, including clear cell renal cell carcinoma (ccRCC). SETD2 deficiency is associated with cancer occurrence and progression by regulating autophagy flux, general metabolic activity, and replication fork speed. Therefore, SETD2 is considered a potential epigenetic therapeutic target and is the subject of ongoing research on cancer-related diagnosis and treatment. This review presents an overview of the molecular functions of SETD2 in H3K36me3 regulation and its relationship with ccRCC, providing a theoretical basis for subsequent antitumor therapy based on SETD2 or H3K36me3 targets.

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“…As the sequential isolation of human α- and β-tubulin depends solely on the affinity tags, this approach applies to studies of tubulin variants (e.g., isotypes and mutants) that could impact the binding to TOG domains or the microtubule polymerization properties. By employing this strategy, current studies have revealed the effects of human β-tubulin isotypes on the microtubule stability and protofilament numbers ( Ti et al, 2018 ) as well as dissected the molecular mechanisms by which methyltransferases modify human α-tubulin ( Kearns et al, 2021 ). Together, the ability to obtain biochemically pure higher eukaryotic tubulin has paved the way to deciphering the functions of tubulin diversity and a clearer understanding of microtubule biology.…”

Section: Introductionmentioning

confidence: 99%

Reconstituting Microtubules: A Decades-Long Effort From Building Block Identification to the Generation of Recombinant α/β-Tubulin

2022

Front. Cell Dev. Biol.

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Microtubules are cytoskeletal filaments underlying the morphology and functions of all eukaryotic cells. In higher eukaryotes, the basic building blocks of these non-covalent polymers, ɑ- and β-tubulins, are encoded by expanded tubulin family genes (i.e., isotypes) at distinct loci in the genome. While ɑ/β-tubulin heterodimers have been isolated and examined for more than 50 years, how tubulin isotypes contribute to the microtubule organization and functions that support diverse cellular architectures remains a fundamental question. To address this knowledge gap, in vitro reconstitution of microtubules with purified ɑ/β-tubulin proteins has been employed for biochemical and biophysical characterization. These in vitro assays have provided mechanistic insights into the regulation of microtubule dynamics, stability, and interactions with other associated proteins. Here we survey the evolving strategies of generating purified ɑ/β-tubulin heterodimers and highlight the advances in tubulin protein biochemistry that shed light on the roles of tubulin isotypes in determining microtubule structures and properties.

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Molecular determinants for α-tubulin methylation by SETD2

Cited by 14 publications

References 67 publications

SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

Reconstituting Microtubules: A Decades-Long Effort From Building Block Identification to the Generation of Recombinant α/β-Tubulin

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