<i>SETD2</i> Haploinsufficiency for Microtubule Methylation Is an Early Driver of Genomic Instability in Renal Cell Carcinoma

Chiang, Yu‐Chun; Park, In Young; Terzo, Esteban A.; Tripathi, Durga Nand; Mason, Frank M.; Fahey, Catherine C.; Karki, Menuka; Shuster, Charles B.; Sohn, Bo Hwa; Chowdhury, Pratim; Powell, Reid T.; Ohi, Ryoma; Tsai, Yi-Hsuan; Cubas, Aguirre A. de; Khan, Abid; Davis, Ian J.; Strahl, Brian D.; Parker, Joel S.; Dere, Ruhee; Walker, Cheryl L.; Rathmell, W. Kimryn

doi:10.1158/0008-5472.can-17-3460

Cited by 53 publications

(48 citation statements)

References 39 publications

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“…We found PBRM1 co-localized with the α-TubK40me3 mark on spindle microtubules made by the SETD2 methyltransferase 8,9 as seen by co-localization of an antibody directed against the α-TubK40me3 mark and GFP-tagged PBRM1 ( Fig. 3a) and confirmed by overlap of the peak intensity of line profiles through the mitotic spindle ( Fig.…”

Section: Pbrm1 Recognizes Methylated α-Tubulinsupporting

confidence: 62%

“…Interestingly, this phenocopied the genomic instability observed in SETD2-null cells that had lost the α-TubK40me3 mark 8,9 .…”

Section: Loss Of Pbrm1 Disrupts Genomic Stabilitymentioning

confidence: 90%

“…Recently, we reported that in addition to histones, the methyltransferase SETD2 (third most frequent driver for ccRCC) also methylates lysine 40 of alpha tubulin (α-TubK40me3) 8,9 . The α-TubK40me3 mark localizes to spindle microtubules during mitosis and to the midbody during cytokinesis.…”

Section: Introductionmentioning

confidence: 99%

“…The α-TubK40me3 mark localizes to spindle microtubules during mitosis and to the midbody during cytokinesis. Loss of SETD2 and α-TubK40me3 causes genomic instability and defects such as multipolar spindle formation, chromosomal bridges at cytokinesis, micronuclei, polyploidy, and polynucleation; a phenotype specifically-linked SETD2 activity as a tubulin methyltransferase 8,9 . However, how the α-TubK40me3 mark on microtubules is "read" to maintain genomic stability is not known.…”

Section: Introductionmentioning

confidence: 99%

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A Cytoskeletal Function for PBRM1 Reading Methylated Microtubules

Karki

Jangid

Seervai

et al. 2020

Preprint

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The chromatin modifier SETD2 was recently shown to be a dual-function methyltransferase that "writes" methyl marks on both chromatin and the mitotic spindle, revealing α-tubulin methylation as a new posttranslational modification of microtubules.Here, we report the first cytoskeletal "reader" for this SETD2 methyl mark: the polybromo protein PBRM1. We found PBRM1 directly binds the α-Tub-K40me3 mark on tubulin, and localizes to the mitotic spindle and spindle pole during cell division. PBRM1 can assemble a PBAF complex in the absence of chromatin as revealed by mass spectrometry, and can recruit other PBAF complex components including SMARCA4 and ARID2 to α-tubulin.In addition to PBRM1, other PBAF components were also localized to the mitotic spindle and spindle pole. This PBAF localization was dependent on recruitment to microtubules by PBRM1, and loss of spindle-associated PBRM1/PBAF led to genomic instability as assessed by increased formation of micronuclei. These data reveal a previously unknown function for PBRM1 beyond its role remodeling chromatin, and expand the repertoire of chromatin remodelers involved in writing and reading methyl marks on the cytoskeleton.The results of this study lay the foundation for a new paradigm for the epigenetic machinery as chromatocytoskeletal modifiers, with coordinated nuclear and cytoskeletal functions.3 Introduction:

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Section: Pbrm1 Recognizes Methylated α-Tubulinsupporting

confidence: 62%

“…Interestingly, this phenocopied the genomic instability observed in SETD2-null cells that had lost the α-TubK40me3 mark 8,9 .…”

Section: Loss Of Pbrm1 Disrupts Genomic Stabilitymentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Cytoskeletal Function for PBRM1 Reading Methylated Microtubules

Karki

Jangid

Seervai

et al. 2020

Preprint

Self Cite

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“…The catalytic SET domain was shown to methylate a-tubulin in vitro, and in dividing cells a-TubK40me3 localized to spindle microtubules and the distal midbody during mitosis and cytokinesis respectively. Loss of SETD2 and the a-TubK40me3 mark led to genomic instability and defects such as multipolar spindle formation, chromosomal bridges at cytokinesis, micronuclei, polyploidy, and polynucleation; a phenotype specifically linked to its activity as a microtubule methyltransferase 14,15 .…”

Section: Introductionmentioning

confidence: 99%

SETD2 is an actin lysine methyltransferase

Seervai

Jangid

Karki

et al. 2020

Preprint

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SET-domain-containing-2 (SETD2) was identified as the methyltransferase responsible for the histone 3 lysine 36 trimethyl (H3K36me3) mark of the histone code. Most recently, SETD2 has been shown to be a dual-function remodeler that regulates genome stability via methylation of dynamic microtubules during mitosis and cytokinesis. Here we show that actin is a bona fide target for methylation by SETD2 in vitro and in cells. Antibodies against the SETD2 trimethyl lysine epitope recognize methylated actin, with this methyl mark localizing to areas of active actin cytoskeleton reorganization in migrating cells. Disruption of this methylation activity causes defects in actin polymerization and impairscollective cell migration. Together, these data identify SETD2 as a multifunctional cytoskeletal remodeler regulating methylation and polymerization of actin filaments, and provide new avenues for understanding how defects in SETD2 drive disease via aberrant cytoskeletal methylation.

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Loss of SETD2 in wild‐type VHL clear cell renal cell carcinoma sensitizes cells to STF‐62247 and leads to DNA damage, cell cycle arrest, and cell death characteristic of pyroptosis

Johnson,

Turcotte

2024

Molecular Oncology

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Loss of chromosome 3p and loss of heterogeneity of the von Hippel–Lindau (VHL) gene are common characteristics of clear cell renal cell carcinoma (ccRCC). Despite frequent mutations on VHL, a fraction of tumors still grows with the expression of wild‐type (WT) VHL and evolve into an aggressive subtype. Additionally, mutations on chromatin‐modifying genes, such as the gene coding for the histone methyltransferase SET containing domain 2 (SETD2), are essential to ccRCC evolution. We previously identified STF‐62247, a small molecule first discovered as a synthetically lethal molecule for VHL‐deficient cells by blocking late stages of autophagy. This study investigated how other commonly mutated genes in ccRCC could impact the response to STF‐62247. We showed that SETD2 inactivation in ccRCC cells expressing WT‐VHL became vulnerable to STF‐62247, as indicated by decreases in cell proliferation and survival. Furthermore, activation of the DNA damage response pathway leads to the loss of M‐phase inducer phosphatase 1 (CDC25A) and cell cycle arrest in S phase. Cleavage of both caspase‐3 and gasdermin E suggests that STF‐62247 eliminates WT‐VHL ccRCC cells through pyroptosis specifically when SETD2 is inactivated.

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SETD2 Haploinsufficiency for Microtubule Methylation Is an Early Driver of Genomic Instability in Renal Cell Carcinoma

Cited by 53 publications

References 39 publications

A Cytoskeletal Function for PBRM1 Reading Methylated Microtubules

A Cytoskeletal Function for PBRM1 Reading Methylated Microtubules

SETD2 is an actin lysine methyltransferase

Loss of SETD2 in wild‐type VHL clear cell renal cell carcinoma sensitizes cells to STF‐62247 and leads to DNA damage, cell cycle arrest, and cell death characteristic of pyroptosis

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