Paracrine HR: Does lactate drive a DNA repair bystander effect?

The radiation bystander effect can involve NHEJ-linked chromosomal aberrations in undamaged neighbor cells (Little et al., 2003). Given that lactate elevates NBS1 lactylation and HR efficiency (Chen et al., 2024), this hypothesis proposes a paracrine “HR priming” effect mediated by lactate export (MCT transporters) or other metabolic cues. Use microfluidic co-cultures where only donor cells are irradiated or nicked (nCas9) and track recipient-cell HR/NHEJ using reporters and RAD51 focus dynamics. Perturb lactate production (LDHA knockdown/inhibitors), export/import (MCT inhibitors), and the TIP60/HDAC3 axis to map causality. This extends bystander research with a mechanistic link from lactylation findings and leverages replication-coupled nicking to control lesion types in donors. If lactate promotes HR in tumor neighborhoods, it could blunt genotoxic therapies by “preconditioning” nearby cells; conversely, blocking lactate signaling could prevent microenvironmental repair enhancement. The impact introduces a new, targetable dimension to the bystander effect with immediate translational implications for radiosensitization.

References:

1. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Hengxing Chen, Yun Li, Hua-fu Li, Xiancong Chen, Hua-Feng Fu, Deli Mao, Wei Chen, Linxiang Lan, Chun-ming Wang, K. Hu, Jia Li, Chengming Zhu, I. Evans, Eddie Cheung, Daning Lu, Yulong He, Axel Behrens, Dong Yin, Changhua Zhang (2024). Nature.
2. Involvement of the Nonhomologous End Joining DNA Repair Pathway in the Bystander Effect for Chromosomal Aberrations. J. Little, H. Nagasawa, Gloria C. Li, David J. Chen (2003). Radiation Research.