Dataset Information

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; aka MPG) 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 is currently unclear how BER efficiently operates on chromatin. Here we show that AAG binds to chromatin and forms a complex with active RNA polymerase (pol) II. This occurs through direct binding to Elongator and results in co-regulation of gene expression. Interestingly, endogenous aberrantly methylated bases accumulate at 3’end of co-regulated genes, in regions enriched for Elongator, active RNA pol II, and BER enzymes AAG and APE1. Active transcription and functional Elongator are further vital to ensure efficient BER by promoting AAG and APE1 chromatin occupancy. Our findings indicate that AAG needs to associate with transcription elongation to maintain genome stability, concurrently coordinating repair with gene expression.

OTHER RELATED OMICS DATASETS IN: GSE129009GSE129010

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryo, Kidney Epithelial Cell

SUBMITTER: Animesh Sharma

LAB HEAD: Barbara van Loon

PROVIDER: PXD013508 | Pride | 2020-05-26

REPOSITORIES: Pride

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

Montaldo Nicola P NP Bordin Diana L DL Brambilla Alessandro A Rösinger Marcel M Fordyce Martin Sarah L SL Bjørås Karine Øian KØ Bradamante Stefano S Aas Per Arne PA Furrer Antonia A Olsen Lene C LC Kunath Nicolas N Otterlei Marit M Sætrom Pål P Bjørås Magnar M Samson Leona D LD van Loon Barbara B

Nature communications 20191129 1

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 ...[more]

PMID: 31784530

Similar Datasets

Project description:Neurodevelopment is a tightly coordinated process, in which genome is exposed to spectra of endogenous agents at different stages of differentiation. Increasing body of evidence suggests that DNA damage is an important feature of developing brain, tightly linked to gene expression programs and neuronal activity. Some of the most frequent DNA damage includes changes to DNA bases, recognized by DNA glycosylases and repaired through base excision repair (BER). The only mammalian DNA glycosylase able to remove frequent alkylated DNA based is alkyladenine DNA glycosylase (Aag, aka Mpg). Recently we showed that, besides participation in DNA repair, AAG affects expression of neurodevelopmental genes in human cells. Aag was further proposed to act as reader of epigenetic marks, including 5-hydroxymethylcytosine (5hmC), in the mouse brain. Despite the evidence of potential Aag involvement in the key brain processes, the impact of Aag loss on developing brain remains unknown. Here, by using Aag knockout (Aag-/-) mice, we show that Aag absence leads to reduced DNA damage levels, evident in lowered number of γH2AX foci in P5 hippocampi. This is accompanied by changes in 5hmC signal intensity in different hippocampal regions. Analysis of gene expression in hippocampus and prefrontal cortex, at multiple developmental stages, indicates that lack of Aag results in altered gene expression, primarily of genes involved in regulation of response to stress. One of the most prominent genes deregulated in Aag-dependent manner, at all tested developmental stages, is aldehyde dehydrogenase 2 (Aldh2). In line with the changes in hippocampal DNA damage levels and the gene expression, adult Aag-/- mice exhibit altered behavior, evident in decreased anxiety in the Elevated Zero Maze and increased alternations in the Elevated T Maze tests. Taken together these results suggests that Aag has functions in modulation of genome dynamics during brain development, important for animal behavior.

			Action	DRS
	L10309_BVL_Flag.RAW	Raw
	L10310_BVL_fAAG.RAW	Raw
	L10311_BVL_fAAG_MMS.RAW	Raw
	L10311_BVL_fAAG_MMS.zip	Other