Dual Chromatin and Cytoskeletal Remodeling by SETD2

Area of Science:

• Cell Biology
• Epigenetics
• Molecular Biology

Background:

• Posttranslational modifications (PTMs) establish distinct
• codes
• for tubulin and histones, governing cellular functions.
• The molecular machinery regulating these codes, particularly
• writers
• and
• erasers
• , were considered separate for the cytoskeleton and epigenome.
• Microtubule PTMs, including acetylation, are crucial for specialized cellular functions.

Purpose of the Study:

• To investigate the role of histone methyltransferases in microtubule modification.
• To determine if SETD2, a known histone methyltransferase, modifies tubulin.
• To elucidate the function of tubulin methylation in cellular processes.

Main Methods:

• Utilized mass spectrometry to identify tubulin methylation.
• Employed genetic deletion of SETD2 in cellular models.
• Observed cellular phenotypes including mitosis, cytokinesis, and genomic stability.

Main Results:

• Identified methylation as a PTM of dynamic microtubules.
• Demonstrated that SETD2 methylates α-tubulin at lysine 40.
• Showed SETD2 deletion leads to defects in mitosis, cytokinesis, and genomic instability (micronuclei, polyploidy).

Conclusions:

• SETD2 is a dual-function enzyme methylating both chromatin (histones) and the cytoskeleton (tubulin).
• Microtubule methylation by SETD2 is essential for mitotic spindle and cytokinesis integrity.
• This study reveals a requirement for tubulin methylation in maintaining genomic stability and coordinating the tubulin and histone codes.