ERCC6 at the Transcription-Replication Interface: Integration of Transcription-Coupled Repair with Replication Stress...

Replication and transcription share the DNA template and must be coordinated to preserve genome integrity. Although temporally organized across the cell cycle, essential transcriptional programs-encoding replication machinery, canonical histones, and DNA repair factors-operate concurrently with DNA synthesis during S phase. Transcription-replication conflicts (TRCs) therefore constitute a recurrent endogenous source of replication stress (RS), particularly under hypertranscriptional or chromatin-constrained conditions. A frequent outcome of TRCs is the formation of R-loops-RNA:DNA hybrids that can stall or collapse replication forks, leading to DNA damage. This review summarizes current evidence supporting a broader involvement of ERCC6/CSB at the transcription-replication interface beyond its established role in transcription-coupled repair. We discuss how ERCC6 participates in RNA polymerase II processing, chromatin remodeling, R-loop metabolism, replication fork protection, and repair pathway engagement following RS, operating through both its ATPase domain and intrinsically disordered regions. Conversely, in homologous recombination-deficient contexts, ERCC6 may favor mutagenic restart mechanisms, including break-induced replication; and recent evidence indicates that ERCC6 status influences cellular fate and the genomic distribution of stress-induced mutations, linking transcription-coupled repair with transcription-dependent mutagenesis. These observations support a model in which ERCC6 coordinates transcription-associated repair with RS responses, shaping genome maintenance and mutational outcomes, with implications for cancer and therapeutic strategies.