Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression

Abstract

Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases, including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here, we show that AAG binds to chromatin and forms complex with RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation. Importantly, at co-regulated genes, aberrantly methylated bases accumulate towards the 3′end in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide insights into genome stability maintenance in actively transcribing chromatin and reveal roles of aberrantly methylated bases in regulation of gene expression.

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…Proteins encoded by Bmi1, Dgcr8, Dicer1, Elp1, Ercc1, Ercc6, Msi1, Sirt6, Top2b, Ubb, and Uchl3 are known to participate in the DNA damage response [387,[389][390][391][392][393][394][395][396][397][398], some in transcription-coupled DNA repair. For example, BMI1 represses transcription at sites of UV-induced DNA damage to allow repair [389]; ELP1 is a required component of the Elongator complex [399], which couples RNA polymerase II to an alkyladenine glycosylase that initiates base excision repair [392]; ERCC6 promotes DSB repair in actively transcribed regions by displacing RNA polymerase from the lesion site [387], and DGCR8 interacts with both RNA polymerase II and ERCC6 to mediate transcription-coupled nucleotide excision repair of UV-induced DNA lesions [390]. Intriguingly, topoisomerase TOP2B, which creates DSBs during transcriptional activation [396], has been identified as a key regulator of transcription during the last stages of postnatal PR development [400].…”

Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin

“…The nesting of the acetylation center within a conserved intrinsically disordered protein domain is a recurrent theme for the PTM-mediated regulation of signaling pathways and chromatin architecture ( 52 ), enabling supramolecular assemblies and liquid–liquid phase transition structures ( 53–55 ), which can organize euchromatin into large transcriptional hubs ( 56 ). Preloading of BER enzymes to chromatin may be required to access base lesions hidden within nucleosome-bound DNA ( 57 , 58 ).…”

DNA alkylation lesion repair: outcomes and implications in cancer chemotherapy

“…(1) Recruitment of AAG on lesions by transcription or replication machinery, as supported by a relative predisposition of BER to occur on the active transcribing or replicating regions (Odell et al, 2013;Bjørås et al, 2017). Biochemical studies showed that AAG interacts with both transcription repressors (e.g., methyl-CpGbinding domain protein 1 (MBD1)) and elongators (e.g., elongator complex protein 1 (ELP1)) (Watanabe et al, 2003;Huttlin et al, 2017;Montaldo et al, 2019). These interactions enhance the AAG-mediated repair along transcription units and may also contribute to localized gene expression (Montaldo et al, 2019).…”

“…Biochemical studies showed that AAG interacts with both transcription repressors (e.g., methyl-CpGbinding domain protein 1 (MBD1)) and elongators (e.g., elongator complex protein 1 (ELP1)) (Watanabe et al, 2003;Huttlin et al, 2017;Montaldo et al, 2019). These interactions enhance the AAG-mediated repair along transcription units and may also contribute to localized gene expression (Montaldo et al, 2019). However, a thoroughly developed genome-wide profiling approach is needed to dissect the distribution of AAG and its associated chaperons in the genome.…”