Base excision repair in chromatin: A tug-of-war for DNA damage

Base excision repair (BER) is a genome surveillance pathway responsible for repairing DNA base lesions distributed throughout the chromatinized eukaryotic genome. However, chromatin structure acts as a dynamic structural barrier that restricts access to DNA and must be overcome for BER to proceed efficiently. In this perspective, we summarize recent advances that have shaped our understanding of BER in chromatin, with a focus on the structural mechanisms employed by core BER enzymes to recognize and repair DNA lesions within the nucleosome. We highlight how DNA accessibility dictates BER enzyme activity and discuss the concepts of localized and global DNA sculpting as emerging strategies for lesion recognition and repair. We propose that BER within the nucleosome represents a molecular "tug-of-war", where the histone octamer and the BER enzymes are in a constant competition for access to the damaged nucleosomal DNA. The outcome of this competition is dictated by the position of the DNA lesion within the nucleosome, which ultimately defines the efficiency of BER enzymes within chromatin. We also explore possible mechanisms used by ATP-dependent chromatin remodeling to facilitate BER within the nucleosome. Together, these recent advances provide a framework for understanding BER in chromatin and outline key unanswered questions regarding chromatin-based BER.