Balancing acts of SRI and an auto-inhibitory domain specify Set2 function at transcribed chromatin

Wang, Yi; Niu, Yanling; Li, Bing

doi:10.1093/nar/gkv393

Cited by 35 publications

(46 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result suggested another level of self-control mechanism that is implemented in the context of the complex. In fact, auto-inhibitory mechanisms are prevalent among chromatin-modifying enzymes (47)(48)(49)(50)(51)(52)(53), which presumably is helpful to establish spatial and temporal specificity of the modification reactions. For instance, H3K36me can be recognized by opposing enzymes Rpd3S and NuA4/Tintin (34, 54) through a common subunit Eaf3.…”

Section: Discussionmentioning

confidence: 99%

Homodimeric PHD Domain-containing Rco1 Subunit Constitutes a Critical Interaction Hub within the Rpd3S Histone Deacetylase Complex

Ruan

Cui

Lee

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Recognition of histone post-translational modifications is pivotal for directing chromatin-modifying enzymes to specific genomic regions and regulating their activities. Emerging evidence suggests that other structural features of nucleosomes also contribute to precise targeting of downstream chromatin complexes, such as linker DNA, the histone globular domain, and nucleosome spacing. However, how chromatin complexes coordinate individual interactions to achieve high affinity and specificity remains unclear. The Rpd3S histone deacetylase utilizes the chromodomain-containing Eaf3 subunit and the PHD domain-containing Rco1 subunit to recognize nucleosomes that are methylated at lysine 36 of histone H3 (H3K36me). We showed previously that the binding of Eaf3 to H3K36me can be allosterically activated by Rco1. To investigate how this chromatin recognition module is regulated in the context of the Rpd3S complex, we first determined the subunit interaction network of Rpd3S. Interestingly, we found that Rpd3S contains two copies of the essential subunit Rco1, and both copies of Rco1 are required for full functionality of Rpd3S. Our functional dissection of Rco1 revealed that besides its known chromatin-recognition interfaces, other regions of Rco1 are also critical for Rpd3S to recognize its nucleosomal substrates and function in vivo. This unexpected result uncovered an important and understudied aspect of chromatin recognition. It suggests that precisely reading modified chromatin may not only need the combined actions of reader domains but also require an internal signaling circuit that coordinates the individual actions in a productive way.It is now widely accepted that histone post-translational modifications (PTMs) 2 and other structural features of chromatin, such as variant histones and DNA modifications, mainly serve as signal platforms to direct downstream regulatory events (1, 2). In general, four major components of chromatin structure contribute to the signals that can be interpreted by downstream chromatin regulators. (i) Histone peptides that carry certain PTMs contribute. Specifically modified histone peptides can be recognized by protein domains/motifs that are commonly referred as PTM "readers." A large repertoire of such domain/PTM interactions have been documented, and they are essential for targeting downstream factors to a given genomic locus (3). Reader domains not only distinguish different types of modifications and the locations of PTMs but also the specific states of modifications. However, due to relatively weak affinity, it is unclear whether these interactions are sufficient to mediate the recruitment of chromatin complexes. For example, although histone H3 methylation at residue Lys-36 (H3K36me) is an essential signal for the histone deacetylase Rpd3S, the contact between the chromodomain of the Eaf3 subunit (CHD Eaf3 ) of Rpd3S and H3K366me only contributes to the binding specificity but not to the overall affinity (4). (ii) Histone globular domains contribute. Because PTMs are mostly cl...

show abstract

Section: Discussionmentioning

confidence: 99%

Homodimeric PHD Domain-containing Rco1 Subunit Constitutes a Critical Interaction Hub within the Rpd3S Histone Deacetylase Complex

Ruan

Cui

Lee

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…This domain is also highly conserved within the family of Set2 enzymes, thus future work is needed to understand how it precisely functions. We speculate, given its close proximity, that the CC domain contributes to a recently described auto-inhibitory domain [18] that controls Set2 methylation output (see below).…”

Section: The Domain Structure Of Set2mentioning

confidence: 97%

“…The SET domain is the catalytic domain of Set2 that performs the H3K36me transfer. Interestingly, although full-length Set2 prefers to methylate nucleosomal substrates, the isolated SET domain can also methylate free histones [18]. Thus, the C-terminus of Set2 is critical for directing substrate specificity (discussed below).…”

Section: The Domain Structure Of Set2mentioning

confidence: 99%

“…As mentioned above, recent studies show that Set2 contains an auto-inhibitory domain (AID) in the region between the SET domain and the WW domain [18]. Deletion of the AID results in a hyperactive Set2, increasing the amount of H3K36me on nucleosomes and at genes.…”

Section: The Domain Structure Of Set2mentioning

confidence: 99%

“…Furthermore, ectopically expressed Set2 truncations lacking the SRI domain still catalyze H3K36me1 and limited amounts of H3K36me2, but they are unable to catalyze H3K36me3 [29]. One explanation for this result may be the ability of the SRI domain to regulate the AID of Set2 that itself antagonizes the SET domain [18]. In Schizosaccharomyces pombe , however, the SRI domain is completely dispensable for H3K36me2, but is required for H3K36me3 and plays a role in post-transcriptional gene silencing at subtelomeric regions of the genome [35].…”

Section: The Domain Structure Of Set2mentioning

confidence: 99%

See 2 more Smart Citations

Shaping the cellular landscape with Set2/SETD2 methylation

McDaniel

Strahl

2017

Cell. Mol. Life Sci.

114

108

View full text Add to dashboard Cite

Chromatin structure is a major barrier to gene transcription that must be disrupted and re-set during each round of transcription. Central to this process is the Set2/SETD2 methyltransferase that mediates co-transcriptional methylation to histone H3 at lysine 36 (H3K36me). Studies reveal that H3K36me not only prevents inappropriate transcriptional initiation from arising within gene bodies, but that it has other conserved functions that include the repair of damaged DNA and regulation of pre-mRNA splicing. Consistent with the importance of Set2/SETD2 in chromatin biology, mutations of SETD2, or mutations at or near H3K36 in H3.3, have recently been found to underlie cancer development. This review will summarize the latest insights into the functions of Set2/SETD2 in genome regulation and cancer development.

show abstract

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

Molenaar

Leeuwen

2022

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

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.

show abstract

Balancing acts of SRI and an auto-inhibitory domain specify Set2 function at transcribed chromatin

Cited by 35 publications

References 49 publications

Homodimeric PHD Domain-containing Rco1 Subunit Constitutes a Critical Interaction Hub within the Rpd3S Histone Deacetylase Complex

Homodimeric PHD Domain-containing Rco1 Subunit Constitutes a Critical Interaction Hub within the Rpd3S Histone Deacetylase Complex

Shaping the cellular landscape with Set2/SETD2 methylation

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

Contact Info

Product

Resources

About