Efficient DNA lesion repair is crucial for cell survival, especially within actively transcribed DNA regions that contain essential genetic information. Additionally, DNA breaks in regions of active transcription are prone to generating insertions and deletions, which are hallmark features of cancer genomes. Cockayne syndrome protein B (CSB) is the sole ATP-dependent chromatin remodeler that is essential for coupling DNA repair pathways with transcription, leading to more efficient DNA repair in regions of active transcription. CSB is best known for its essential function in transcription-coupled nucleotide excision repair (TC-NER), a process that rapidly removes helix-distorting DNA lesions that stall RNA polymerase II, such as those created by chemotherapeutic platinum compounds and UV irradiation. In addition to NER, CSB has also been reported to couple homologous recombination to transcription. Most recently, CSB has also been shown to couple single-strand DNA break repair to transcription. In this review, we will discuss the overlapping and distinct mechanisms by which CSB couples these different DNA repair pathways to transcription. We will also discuss how these CSB functions may account for Cockayne syndrome and the emerging roles of CSB as an innovative target for cancer therapy.

A cornerstone of research to improve cancer outcomes involves studies of model systems to identify causal drivers of oncogenesis, understand mechanisms leading to metastases, and develop new therapeutics. While most cancer types are represented by large cell line panels that reflect diverse neoplastic genotypes and phenotypes found in patients, prostate cancer is notable for a very limited repertoire of models that recapitulate the pathobiology of human disease. Of these, Lymph node carcinoma of the prostate (LNCaP) has served as the major resource for basic and translational studies. Here, we delineated the molecular composition of LNCaP and multiple substrains through analyses of whole genome sequences, transcriptomes, chromatin structure, AR cistromes, and functional studies. Our results determined that LNCaP exhibits substantial subclonal diversity, ongoing genomic instability and phenotype plasticity. While several oncogenic features were consistently present across strains, others were unexpectedly variable such as ETV1 expression, Y chromosome loss, a reliance on WNT and glucocorticoid receptor activity, and distinct AR alterations maintaining AR pathway activation. These results document the inherent molecular heterogeneity and ongoing genomic instability that drive diverse prostate cancer phenotypes and provide a foundation for the accurate interpretation and reproduction of research findings.