Cancer patients undergoing certain chemotherapies often report a series of neurotoxic side effects, collectively referred to as “chemobrain.” These effects often include brain “fog” including difficulties with memory, concentration, and more. What could be the culprit behind these symptoms?
In this article:
- How active DNA demethylation, a key epigenetic process, functions
- The link between the regulation of DNA methylation and the neurotoxic single-strand DNA breaks that may be behind chemobrain
What is active DNA demethylation?
The methylation of cytosine (5-mC) in genomic DNA is an epigenetic modification that plays a role in many different biological processes, such as embryogenesis and cellular differentiation. Active DNA demethylation is a biological pathway that removes 5-mC from genomic DNA to replace it with the un-methylated cytosine- almost like a molecular “on-off” pathway. This intricate process involves many proteins, with the key player being thymine DNA glycosylase (TDG) and members of the ten-eleven translocation (TET) family of dioxygenases.
Active DNA demethylation and single strand DNA breaks
The removal of 5-mC has been known to generate transient single-strand breaks (SSB) in genomic DNA, which triggers a DNA repair pathway called base excision repair (BER). Active DNA demethylation has typically been studied in vitro using cell culture techniques. However, the in vivo and physiological significance of SSB and BER in active DNA demethylation has remained unclear.
A recent paper published in Science showed that SSBs generated during active DNA demethylation are dependent on the TDG enzyme. Accumulation of these breaks can cause cell death, as well as defects during and after cellular differentiation. Using novel high throughput sequencing techniques, including synthesis-associated repair sequencing (SARseq) and S1-END-seq, the authors showed that SSBs are localized to DNA elements called enhancers, which are often targets of active DNA demethylation.
What causes these SSBs to accumulate? The authors point to a failure of the DNA repair system, which is disrupted by many chemotherapeutic agents. The authors propose that when this normally protective pathway gets disrupted by chemotherapy, blocking TDG may prevent the generation of single-strand breaks. These findings potentially help explain and provide therapeutic direction to the long-standing mystery in oncology as to why some antimetabolite chemotherapies, such as cytarabine, lead to the characteristic thinking and memory problems of chemobrain.
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Haider M. Hassan, Data Scientist, Bridge Informatics
Haider is one of our premier data scientists. He provides bioinformatic services to clients, including high throughput sequencing, data pre-processing, analysis, and custom pipeline development. Drawing on his rich experience with a variety of high-throughput sequencing technologies, Haider analyzes transcriptional (spatial and single-cell), epigenetic, and genetic landscapes.
Before joining Bridge Informatics, Haider was a Postdoctoral Associate at the London Regional Cancer Centre in Ontario, Canada. During his postdoc, he investigated the epigenetics of late-onset liver cancer using murine and human models. Haider holds a Ph.D. in biochemistry from Western University, where he studied the molecular mechanisms behind oncogenesis. Haider still lives in Ontario and enjoys spending his spare time visiting local parks. If you’re interested in reaching out, please email [email protected] or [email protected].
