SETD2 safeguards the genome against isochromosome formation

Area of Science:

• Genetics
• Epigenetics
• Cancer Biology

Background:

• Isochromosomes, characterized by duplicated and deleted genetic material, are frequently observed in cancers and developmental disorders, contributing to genome instability.
• The precise mechanisms preventing isochromosome formation remain largely unknown, hindering our understanding of their role in disease.
• SETD2, a tumor suppressor, plays a critical role in epigenetic regulation through histone methylation.

Purpose of the Study:

• To investigate the role of the tumor suppressor SETD2 in preventing the formation of isochromosomes.
• To elucidate the contribution of the epigenetic mark H3K36me3, regulated by SETD2, in maintaining genome stability.
• To understand the molecular mechanisms underlying isochromosome generation in the absence of functional SETD2.

Main Methods:

• Utilized cellular and cytogenetic approaches to analyze chromosome aberrations.
• Assessed the impact of SETD2 loss and H3K36me3 deficiency on chromosome structure.
• Investigated the potential involvement of homologous recombination pathways, specifically RAD52, in the observed defects.

Main Results:

• Loss of SETD2 or its associated epigenetic mark, histone H3 lysine 36 trimethylation (H3K36me3), significantly increases the formation of isochromosomes.
• Defects including isodicentric and acentric chromosomes were observed upon SETD2 or H3K36me3 loss.
• Evidence suggests that DNA replication errors and faulty homologous recombination mediated by RAD52 contribute to isochromosome generation.

Conclusions:

• SETD2 and its H3K36me3 mark are essential for preventing the formation of isochromosomes.
• The study provides a mechanistic link between SETD2 function, epigenetic regulation, and genome stability.
• These findings highlight SETD2 as a crucial barrier against the generation of mutable chromatin structures that drive genomic instability in cancer.