Transcription coupled base excision repair in mammalian cells: So little is known and so much to uncover

• Published in: DNA repair 2021-11, Vol.107, p.103204, Article 103204
• Main Authors: Chakraborty, Anirban, Tapryal, Nisha, Islam, Azharul, Mitra, Sankar, Hazra, Tapas
• Format: Article
• Language: English
• Subjects: Animals; Base excision repair; DNA - metabolism; DNA Damage; DNA glycosylase; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA Repair; Human Nei like proteins (NEILs); Humans; Oxidation-Reduction; Oxidative DNA damage; Transcription coupled repair; Transcription, Genetic
• ISSN: 1568-7864; 1568-7856; 1568-7856
• DOI: 10.1016/j.dnarep.2021.103204

•NEIL2 is involved in the preferential repair of oxidized DNA base lesions from the actively transcribed genes in mammals.•BER enzymes function as a preformed complex with multiple other proteins forming a “BERosome”.•NEIL2 has anti-inflammatory function in addition to its role in TC-BER.•TC-BER can be reconstituted in vitro using purified NEIL2, PNKP, Pol β, Ligase IIIα, RNAPII and essential transcription factors.•TC-BER deficiency can be linked to various human pathological conditions. Oxidized bases in the genome has been implicated in various human pathologies, including cancer, aging and neurological diseases. Their repair is initiated with excision by DNA glycosylases (DGs) in the base excision repair (BER) pathway. Among the five oxidized base-specific human DGs, OGG1 and NTH1 preferentially excise oxidized purines and pyrimidines, respectively, while NEILs remove both oxidized purines and pyrimidines. However, little is known about why cells possess multiple DGs with overlapping substrate specificities. Studies of the past decades revealed that some DGs are involved in repair of oxidized DNA base lesions in the actively transcribed regions. Preferential removal of lesions from the transcribed strands of active genes, called transcription-coupled repair (TCR), was discovered as a distinct sub-pathway of nucleotide excision repair; however, such repair of oxidized DNA bases had not been established until our recent demonstration of NEIL2’s role in TC-BER of the nuclear genome. We have shown that NEIL2 forms a distinct transcriptionally active, repair proficient complex. More importantly, we for the first time reconstituted TC-BER using purified components. These studies are important for characterizing critical requirement for the process. However, because NEIL2 cannot remove all types of oxidized bases, it is unlikely to be the only DNA glycosylase involved in TC-BER. Hence, we postulate TC-BER process to be universally involved in maintaining the functional integrity of active genes, especially in post-mitotic, non-growing cells. We further postulate that abnormal bases (e.g., uracil), and alkylated and other small DNA base adducts are also repaired via TC-BER. In this review, we have provided an overview of the various aspects of TC-BER in mammalian cells with the hope of generating significant interest of many researchers in the field. Further studies aimed at better understanding the mechanistic aspects of TC-BER could help elucidate the linkage