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Our genetic material is constantly threatened by cell metabolites or exogenous agents triggering various types of base modifications, such as 7,8-dihydro-8-oxoguanine (8-oxoG) 3-methyladenine (3meA) and 7-methylguanine (7meG). Endogenously thousands of 8-oxoG, 3meA and 7meG lesions are generated in each cell of our body, primaraly by reactive oxygen and nitrogen species (RONS). These base lesions promote genomic instability and if unrepaired contribute to development of multiple diseases including cancers, inflammatory diseases or neurodegenerative pathologies. Base lesions are handled by the base excision repair (BER) pathway. To initiate this repair pathway, two glycosylases are in charge of damaged base detection and excision: 8-oxoG DNA glycosylase 1(OGG1) for  8-oxoG, and alkyladenine DNA glycosylase (AAG/MPG)  for 3meA and 7meG. While other repair factors are also important  to restore the original DNA sequence, these two DNA glycosylases are crucial for genome stability maintanance. To recognize and remove base lesions DNA glycosylases face a paradoxical challenge; they must display high specificity and at the same time need to rapidly sample the DNA to ensure the timely lesion detection. While current data suggests that multiple cues regulate the efficient detection and excision of base lesions by OGG1 and AAG, we still miss an integrated picture of these different regulatory mechanisms. By associating labs with complementary expertise, our current project aims to progress in the understanding of these mechanisms by studying them at multiple scales in space and time.

Investigating the lesion-seeking mechanisms of the DNA glycosylases OGG1 and AAG

Neurodevelopment is a spatially and temporally coordinated process dependent on tightly regulated gene expression. The changes in gene expression are important for generation of functional neurons and of a brain as whole. Besides epigenetic DNA methylation, regulating gene expression, in each neuron of our brain several thousands of aberrantly methylated DNA bases are generated every day. Our work indicated that aberrantly methylated bases, together with enzymes that repair them, accumulate in defined regions of neurodevelopmental genes. In addition, active DNA repair was indicated to characterise healthy neurons and to occur in regions of the genome relevant for neuronal development and function. Despite the links between neuronal health and DNA repair, our knowledge is still surprisingly limited about neuronal genome dynamics and strategies that ensure neuronal distinct longevity. The main aim of this project is to determine the function of aberrant DNA methylation in shaping of the neuronal genome. The project results suggest important regulatory crosstalk between enzymes involved in processing of epigenetic and aberrantly methylated DNA bases. We further show that loss of DNA glycosylases, the central enzymes in this process, results in dysregulation of neurodevelopmental gene expression, leading to global neuronal and brain dysfunction. The long-term goal of this study is to reveal new mechanisms of neuronal genome dynamics, with direct implications for brain development and health.

In each neuron of our brain several thousands of aberrantly methylated DNA bases are generated every day. Alkyladenine DNA glycosylase (AAG) is a key enzyme for removal of aberrantly methylated bases and subsequent initiation of base excision repair (BER). DNA repair in neurons occurs primarily in actively transcribed genes. Global increase in aberrant DNA bases is associated with decline in neuronal function and age-specific changes in gene expression. Unexpectedly, active DNA repair occurring in defined regions of the genome, relevant for neuronal development and function, has recently been indicated as an important characteristic of healthy neurons. Consistent with this, our recent work and preliminary findings suggest that aberrantly methylated bases accumulate in defined regions of the genome and have functional roles. Importantly, accumulation of aberrantly methylated bases alters status of epigenetic DNA marks and histone modifications in defined regulatory elements. Co-occurrence of aberrantly methylated and epigenetic DNA bases has potential to alter binding of specific transcription factors, as well as activity of enzymes important for chromatin maintenance. Inability to repair aberrantly methylated bases and their consequent accumulation perturb expression of neurodevelopmental genes. Despite the links between neuronal health and DNA repair, our knowledge is still surprisingly limited about neuronal genome dynamics, precise distribution of aberrantly methylated bases, and strategies evolved to ensure neuronal distinct longevity. In this project, I aim to determine the function of aberrant and epigenetic DNA methylation in shaping of the neuronal genome and ensuring regulated gene expression. Identification of the new concept in regulation of gene expression dependent on the information from aberrant and epigenetic DNA bases, will reveal new layers in neuronal genome dynamics, with direct implications for brain development and health.

Function of aberrant DNA methylation in shaping neuronal genome during neurodevelopment

Numerous lethal and mutagenic DNA lesions are formed in each cell of our body, every day. DNA base damage is generated upon exposure to damaging agents present in our environment, food, water and inside cells as natural metabolites. The accumulation of DNA base damage is considered to contribute to the onset of neurological disorders, cancer and to promote ageing. Base excision repair (BER) is the major pathway for the removal of damaged DNA bases. The specificity of BER is determined by DNA glycosylases that recognize damaged bases and initiate the pathway. Besides their role in the genome integrity maintenance increasing amount of evidence indicates that DNA glycosylases modulate gene expression. It is currently however unknown how DNA glycosylases regulate the gene expression. With this project we aim to explore the mechanisms underlying DNA glycosylase dependent transcription regulation. During the course of this project we have discovered that DNA glycosylase AAG associates with actively transcribing RNA polymerase II, through direct binding to the Elongator complex. We further showed that this interaction ensures functional AAG-initiated repair, as well as impacts gene expression, in particular of neurodevelopmental genes. The analysis of AAG role in neurodevelopment indicated that altered AAG status impacts gene expression and DNA damage status. In summary, results of this project shed light on the non-canonical role of DNA glycosylases in regulation of transcriptional programs and gene expression.

In this project I aim to challenge current thinking and by using multi-disciplinary approach to explore how DNA glycosylases act beyond classical DNA repair by regulating gene expression. Base excision repair (BER) is the major pathway for the removal of damaged DNA bases. DNA base damage is generated upon exposure to damaging agents present in our environment, food, water and inside cells as natural metabolites. The accumulation of DNA damage is considered to contribute to the onset of neurodevelopmental disorders, cancer and to promote ageing. The specificity of BER is determined by DNA glycosylases that recognize damaged bases and initiate the pathway. The current view is that a major role of DNA glycosylases is to prevent the fixation of mutations and thus protect against degenerative processes and diseases, such as cancer. However, loss of DNA glycosylases does not lead to premature ageing and only in certain instances results in higher cancer incidence. Interestingly, recent work and our unpublished findings show that loss of DNA glycosylases impairs the gene expression. These results suggest that one fundamental function of DNA glycosylases is to regulate transcriptional networks and suggest DNA glycosylases as possibly important modulators of developmental processes. It is currently unknown how DNA glycosylases regulate the gene expression and consequently affect development. The main hypothesis of the project is that DNA glycosylases, by recognizing damaged DNA bases, regulate gene expression. The aim is to determine molecular mechanisms of DNA glycosylases in coordinating the effect of environmental signals on transcription regulation. We expect that the results from this project will delineate the adverse effects of DNA glycosylase loss on development.

Mechanisms underlying DNA glycosylase dependent regulation of gene expression

3 projects

INTSAMARBEID-INTSAMARBEID

Investigating the lesion-seeking mechanisms of the DNA glycosylases OGG1 and AAG

Awarded: NOK 68,999

Project Period: 2026-2027

Location: Trøndelag - Trööndelage

FRIPROSJEKT-FRIPROSJEKT

Function of aberrant DNA methylation in shaping neuronal genome during neurodevelopment

Awarded: NOK 9.6 mill.

Project Period: 2022-2028

Location: Trøndelag - Trööndelage

FRIMEDBIO-Fri prosjektstøtte for medisin, helse og biologi

Mechanisms underlying DNA glycosylase dependent regulation of gene expression

Awarded: NOK 8.1 mill.

Project Period: 2017-2021

Location: Trøndelag - Trööndelage