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

Authors :
W. Kimryn Rathmell
Cheryl L. Walker
Ruhee Dere
Joel S. Parker
Brian D. Strahl
Ian J. Davis
Abid Khan
Aguirre A. de Cubas
Yihsuan S. Tsai
Ryoma Ohi
Reid T. Powell
Pratim Chowdhury
Bo-Hwa Sohn
Charles B. Shuster
Menuka Karki
Catherine C. Fahey
Frank M. Mason
Durga Nand Tripathi
Esteban A. Terzo
In-Young Park
Yun-Chen Chiang
Publication Year :
2023
Publisher :
American Association for Cancer Research (AACR), 2023.

Abstract

Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase SETD2, which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (αTubK40me3) during mitosis, with αTubK40me3 required for genomic stability. We now show that monoallelic, Setd2-deficient cells retaining H3K36me3, but not αTubK40me3, exhibit a dramatic increase in mitotic defects and micronuclei count, with increased viability compared with biallelic loss. In SETD2-inactivated human kidney cells, rescue with a pathogenic SETD2 mutant deficient for microtubule (αTubK40me3), but not histone (H3K36me3) methylation, replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show that the SETD2 tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability.Significance: Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underscoring the growing relevance of tumor suppressor haploinsufficiency in tumorigenesis. Cancer Res; 78(12); 3135–46. ©2018 AACR.

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....5b405439d92a4d44007c6c967ae1a3cf
Full Text :
https://doi.org/10.1158/0008-5472.c.6510453