# HAT1 functions as a lactyltransferase and mediates RPA1 lactylation to promote DNA repair and radioresistance in lung adenocarcinoma

## TL;DR

This study shows that HAT1 promotes DNA repair and radioresistance in lung cancer by lactylating RPA1, a key protein in DNA repair.

## Contribution

The study identifies HAT1 as a lactyltransferase that regulates RPA1 lactylation to influence DNA repair and cancer radioresistance.

## Key findings

- HAT1 promotes homologous recombination and radioresistance by lactylating RPA1.
- Lactylation of RPA1 enhances its interaction with DNA and MRN complexes.
- HAT1 knockout reduces DNA repair and increases radiotherapy sensitivity in lung cancer cells.

## Abstract

Lysine lactylation is a post-translational modification induced by lactate discovered in recent years. Abnormal lysine lactylation contributes to the occurrence and progression of various tumors. However, the mediators and downstream targets of lysine lactylation remain unclear. Here, we report that HAT1 serves as a potential lactyltransferase that can promote homologous recombination and lead to radioresistance by regulating lactylation of RPA1. Lactylation of RPA1 facilitates its binding to single-stranded DNA and MRE11-RAD50-NBS1 (MRN) complexes and promotes homologous recombination. HAT1 knockout inhibits DNA repair in lung adenocarcinoma cells, thereby increasing radiotherapy sensitivity. Interestingly, we also found that K15 auto-lactylation of HAT1 can modulate its lactyltransferase activity. In conclusion, our research reveals that HAT1-regulated RPA1 lactylation plays an important role in homologous recombination and radioresistance, suggesting that HAT1 may become a potential therapeutic target for reversing the radioresistance caused by lactate accumulation in cancer cells.