The role of transcription-coupled nucleotide excision repair (TC-NER) during mammalian forebrain development

Mechanisms that maintain genome integrity are crucial for coordinating transcription that drives mammalian forebrain development. Neural progenitor cells and differentiating neurons in the developing forebrain sustain high transcriptional activity and metabolic demand and are therefore vulnerable to DNA damage. Transcription-coupled nucleotide excision repair is a specialized DNA repair pathway that helps to mitigate damage induced by 'bulky' adducts such as UV-induced pyrimidine dimers and monoadducts formed by reactive oxygen species. TC-NER factors, which include CSB/CSA, UVSSA-USP7, ELOF1, and STK19, coordinate and assemble the complex to initiate repair. Notably, TC-NER safeguards genome integrity and plays an essential role in neuronal differentiation, synaptogenesis, and neurogenesis. Impaired TC-NER pathway activity manifests in tissue-level pathologies, including neurodegeneration and increased susceptibility to neurological deficits. This is relevant to neurodevelopmental disorders that stem from TC-NER deficiency, such as Cockayne syndrome, Trichothiodystrophy, and Cerebro-Oculo-Facio-Skeletal syndrome. Although deficits in TC-NER have been well established as a contributor to a variety of neurodegenerative disorders, its roles in the developing forebrain across various cell types and neurodevelopmental windows remain poorly defined. In this review, we highlight recent studies investigating mechanisms linking TC-NER deficiency to forebrain developmental phenotypes and summarize knowledge gaps in the field regarding cell-type specificity, regional vulnerability, and therapeutic windows for intervention.