Human HDAC6 senses valine abundancy to regulate DNA damage

Area of Science:

• Molecular Biology
• Cancer Biology
• Biochemistry

Background:

• Valine, an essential branched-chain amino acid, is crucial for protein synthesis, neurological function, and hematopoiesis.
• The cellular mechanisms for sensing valine abundance and its downstream effects remain largely unknown.
• Understanding valine sensing is critical for elucidating its role in physiological processes and diseases like leukemia.

Purpose of the Study:

• To identify the molecular sensor responsible for detecting intracellular valine levels.
• To elucidate the mechanism by which valine sensing influences cellular functions, particularly DNA integrity.
• To explore the therapeutic potential of manipulating valine levels in cancer treatment.

Main Methods:

• Biochemical assays to demonstrate direct binding of valine to HDAC6.
• Cellular fractionation and imaging to track HDAC6 localization under varying valine conditions.
• DNA damage assays and analysis of DNA demethylation markers (TET2, TDG).
• In vivo studies using xenograft and patient-derived xenograft models with dietary valine restriction.

Main Results:

• Human histone deacetylase 6 (HDAC6) directly binds valine via a primate-specific domain, functioning as a valine sensor.
• Intracellular valine levels control the nuclear-cytoplasmic shuttling of human HDAC6.
• Valine deprivation causes nuclear retention of HDAC6, leading to TET2 deacetylation, active DNA demethylation, and subsequent DNA damage.
• Dietary valine restriction suppressed tumor growth in preclinical models and improved PARP inhibitor efficacy.

Conclusions:

• Human HDAC6 serves as a critical sensor for intracellular valine, linking nutrient status to DNA integrity.
• HDAC6-mediated regulation of DNA demethylation and damage in response to valine deprivation is a novel biological pathway.
• Dietary valine restriction represents a promising strategy for cancer therapy, potentially enhancing existing treatments like PARP inhibitors.