SETD2 Safeguards the Genome Against Isochromosome Formation

Authors

Frank M Mason
Emily S Kounlavong
Anteneh T Tebeje
Rashmi Dahiya
Tiffany Guess
Abid Khan
Logan Vlach
Stephen R Norris
Courtney A Lovejoy
Ruhee Dere
Brian D Strahl
Ryoma Ohi
Peter Ly
Cheryl Lyn Walker
W Kimryn Rathmell

Publication Date

9-26-2023

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2303752120

PMID

37722039

PMCID

PMC10523680

PubMedCentral® Posted Date

9-18-2023

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Humans, Centromere, Chromosome Aberrations, Cytogenetics, DNA Replication, Genomic Instability, Isochromosomes, chromosome, mitosis, isochromosome, intratumoral heterogeneity, epigenetics

Abstract

Isochromosomes are mirror-imaged chromosomes with simultaneous duplication and deletion of genetic material which may contain two centromeres to create isodicentric chromosomes. Although isochromosomes commonly occur in cancer and developmental disorders and promote genome instability, mechanisms that prevent isochromosomes are not well understood. We show here that the tumor suppressor and methyltransferase SETD2 is essential to prevent these errors. Using cellular and cytogenetic approaches, we demonstrate that loss of SETD2 or its epigenetic mark, histone H3 lysine 36 trimethylation (H3K36me3), results in the formation of isochromosomes as well as isodicentric and acentric chromosomes. These defects arise during DNA replication and are likely due to faulty homologous recombination by RAD52. These data provide a mechanism for isochromosome generation and demonstrate that SETD2 and H3K36me3 are essential to prevent the formation of this common mutable chromatin structure known to initiate a cascade of genomic instability in cancer.

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