Mutagenesis

General Description of the lab

The focus of our laboratory is to comprehensively address the various metabolic processes that occur on DNA, which influence the generation and repair of genomic damage, in order to understand the genesis of mutations with the potential to generate therapy-related secondary tumors, as well as neurodegenerative diseases. Through this integration, we intend to identify new therapeutic targets that represent vulnerabilities for the development and progression of altered cells on which to design new targeted therapies.

Chair: Marcelo de Campos Nebel, PhD
Research Scientist from CONICET.

mnebel@hematologia.anm.edu.ar

Download CV

Co-Chair: Marcela Beatriz González Cid, PhD

Research Scientist from CONICET.

margoncid@hematologia.anm.edu.ar

Download CV

Researchers

Fellows

Research

Research projects

The nature of the DNA double helix requires the constant removal of topological barriers to allow various metabolic processes to take place within the nucleus that are necessary for cellular life. Topoisomerases (Top) achieve this through the temporary interruption of genome integrity and subsequent restoration of the continuity of the DNA double helix. In this way, Topoisomerases form transient phosphodiester bonds with 3′ ends (Top1) or 5′ ends (Top2) of DNA. Several chemotherapeutic agents and certain genomic lesions increase the half-life of these DNA-bound enzymes and generate protein blocks at the DNA ends. These structures require specialized removal mechanisms to enable their repair. The progression of DNA replication forks as well as the passage of the transcriptional machinery can be disrupted by these protein blocks, leading to stalling or collapse of these structures. This can delay the mentioned processes or even result in harmful genomic lesions that require repair to prevent the generation of mutations. The removal of protein blocks from DNA ends requires both nucleolytic and hydrolytic activities. In the former case, nucleolytic cleavage of a DNA segment containing the blocking protein takes place, eventually resulting in the loss of genetic material. On the other hand, cellular hydrolases (TDP1 and TDP2) are capable of directly removing phosphodiester bonds between the blocking proteins and DNA. Alterations in these processes may be responsible for resistance to oncology therapies or even neurodegenerative conditions.

The current research projects being carried out in our laboratory can be summarized as follows:

Identification of the molecular and cellular mechanisms responsible for the removal of cleavage complexes stabilized by Top2 poisons. (Aznar/de Campos Nebel)
Evaluation of the effect of chromatin states on the repair activity of Tyrosyl-DNA phosphodiesterases in response to Top2 poisons. (Gosso/de Campos Nebel)
Analysis of the interplay of DNA damage response (DDR) elements that maintain genome integrity against damage generated by Top2 poisons. (Segovia/González Cid).

Publications