Visual Universitätsmedizin Mainz

Dr. Andriy Khobta

Responses to DNA lesions

DNA damage is a well-recognised causal factor of gene dysfunction in the pathogenesis of cancers and age-related diseases. Exposed to reactive endogenous metabolites and environmental toxicants, DNA of all living cells continuously suffers chemical alterations. Dozens of structurally different modifications (“DNA lesions”) have been identified to date; however, repair and other responses to DNA damage have been satisfactorily characterised for just a few. Our group specialises in the assessment of repair and functional consequences of structurally defined DNA lesions.

 

We exploit synthetic nucleotide derivatives that exactly correspond to structures of biologically highly relevant DNA modifications induced by food carcinogens, drugs, environmental toxicants and endogenous cellular mechanisms. We have developed procedure for efficient incorporation of such synthetic DNA lesions into functional reporter gene elements (Lühnsdorf et al. 2012). To understand the lesion-specific repair mechanisms and harmful consequences of individual lesions, we deliver these gene constructs to host cells in which defined components of DNA repair or DNA damage response pathways are impaired by pre-existing genetic defects (cells derived from patients) or have been artificially compromised (by genetic tools or inhibitors). Current projects follow three major directions:

 

•   Fundamental mechanisms of DNA repair – nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR).

 

•   Epigenetic and regulatory functions of DNA base modifications – dynamics of DNA modifications and transcriptional responses in the context of functional gene promoters.

 

•   DNA damage as causal factor of disease – links between the DNA adducts induced by exposures to exogenous genotoxic insults (environment, lifestile, diet, medications, etc.) and the aetiology of human diseases associated with hereditary DNA repair defects (Xeroderma pigmentosum, Cockayne syndrome and several other neurological and degenerative diseases)

 

On the long run, the knowledge of molecular and cellular mechanisms underlying the outcomes of lesion-specific responses to DNA damage shall help to characterise hazards of exposure to specific genotoxic agents and identify molecular susceptibility markers (for prevention of diseases) as well as potential targets for personalised therapeutic interventions (for instance, cytotoxic treatments of tumours).

 

To learn more about the team and our research, please navigate to the lab web site: Laboratory "Responses to DNA lesions"

 

Our team takes part in the International PhD Programme and the International Summer School hosted by the Institute of Molecular Biology (IMB, Mainz).

 

 

 

 

 

Figure 1 | Expression vectors containing the elements of synthetic nucleic acid as a tool for understanding the repair and functional impact of structurally defined DNA base modifications.

 

Featured publications

Kitsera N, Allgayer J, Parsa E, Geier N, Rossa M, Carell T, Khobta A (2017). Functional impacts of 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxycytosine at a single hemi-modified CpG dinucleotide in a gene promoter. Nucleic Acids Res (in press), doi: 10.1093/nar/gkx718

 

Allgayer J, Kitsera N, Bartelt S, Epe B, Khobta A (2016). Widespread transcriptional gene inactivation initiated by a repair intermediate of 8-oxoguanine. Nucleic Acids Res 44(15): 7267-7280.

 

Lühnsdorf B, Epe B, Khobta A (2014) Excision of uracil from transcribed DNA negatively affects the gene expression. J Biol Chem, 289, 22008-22018

 

Kitsera N, Gasteiger K, Lühnsdorf B, Allgayer J, Epe B, Carell T, Khobta A (2014) Cockayne syndrome: varied requirement of transcription-coupled nucleotide excision repair for the removal of three structurally different adducts from transcribed DNA. PLoS One, 9, e94405

 

Lhnsdorf B, Kitsera N, Warken D, Lingg T, Epe B, Khobta A (2012) Generation of reporter plasmids containing defined base modifications in the DNA strand of choice. Anal Biochem 425(1): 47-53

 

Allgayer J, Kitsera N, von der Lippen C, Epe B, Khobta A (2013) Modulation of base excision repair of 8-oxoguanine by the nucleotide sequence. Nucleic Acids Res, 41, 8559-8571

 

Kitsera N, Stathis D, Lühnsdorf B, Müller H, Carell T, Epe B, Khobta A (2011) 8-oxo-7,8-dihydroguanine in DNA does not constitute a barrier to transcription but is converted into transcription-blocking damage by OGG1. Nucleic Acids Res, 39, 5926-5934

 

Khobta A, Anderhub S, Kitsera N, Epe B (2010) Gene silencing induced by oxidative DNA base damage: association with local decrease of histone H4 acetylation in the promoter region. Nucleic Acids Res, 38, 4285-4295 [Open access to full text]

 

 

 

Publication list (PubMed)

 

Brief CV (Andriy Khobta)

 

Research funding