Loss of lactate dehydrogenase A disrupts R-loop homeostasis and induces DNA damage in breast cancer cells.

Loss of LDHA disrupts R-loop homeostasis and induces DNA damage in breast cancer cells, with 199 peaks increased and 81 decreased in 4T1 cells.

• Why it matters: Understanding how R-loops are regulated is crucial because their imbalance can lead to genome instability, which is linked to cancer progression. The role of LDHA, a key glycolytic enzyme and atypical DNA-binding protein, in this process remains unclear.
• What they did: The study used CUT&Tag-seq to map R-loops and LDHA binding sites, RNA-seq for gene expression profiling, and immunofluorescence and Western blotting to analyze protein levels and localization in wild-type and LDHA knockout 4T1 cells.
• The result: LDHA knockout caused R-loop accumulation and DNA damage, which were reversed by RNase H1, indicating LDHA’s role in R-loop regulation through direct DNA binding beyond its metabolic function.