The Lactate-DDR Switch: A post-translational “code” that rewires DSB pathway choice across metabolic states

Building on Chen et al. (Nature, 2024) showing TIP60-mediated lactylation of NBS1 K388 is required for MRN assembly and HR, systematically map the DDR “lactylome” after DNA damage and metabolic perturbations (Warburg-like lactate, hyperglycemia). Use quantitative acyl-proteomics and CRISPR K→R/E mutagenesis at candidate DDR proteins (e.g., NBS1, MRE11, RAD50, BRCA1, 53BP1, RPA, XRCC4) to determine how lactylation toggles HR, c-NHEJ, MMEJ, or SSA. Functionally couple this to pathway reporters and long-read sequencing of repair outcomes. This extends Chen et al. beyond a single modification to a network model; overlays conditions known to alter DDR (hyperglycemia, Warburg lactate) and tumor-context modulators (BRCA1/WWOX status). A metabolic-PTM switch could explain why HR is unexpectedly efficient in lactate-rich tumors and why high glucose increases mutational load yet yields chemo/radioresistance. If validated, targeting lactate production (e.g., LDHA inhibition with stiripentol) or TIP60/HDAC3 selectivity could deliberately bias repair toward error-prone routes in cancer (sensitization) or toward high-fidelity routes in normal tissues (protection). This research could provide a unifying framework linking cancer metabolism to DNA repair pathway choice, with immediately testable therapeutic levers.

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. Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection. Tirza Bidany-Mizrahi, Aya Shweiki, Kian Maroun, Lina Abu-Tair, Bella Mali, R. Aqeilan (2024). Cell Death Discovery.
3. Aberrant DNA damage response and DNA repair pathway in high glucose conditions.. Amy Zhong, Melissa H Y Chang, T-H Yu, Raymond Gau, D. Riley, Yumay Chen, Phang-lang Chen (2018). Journal of Cancer Research Updates.