Tardigrade-Specific DNA Binding Protein TDR1 is Induced and Enhances Resistance to Ionizing Radiation

Core Concepts

Tardigrade-specific DNA binding protein TDR1 is strongly upregulated in response to ionizing radiation and contributes to the remarkable radio-resistance of tardigrades.

Abstract

The study aimed to understand the mechanisms underlying the exceptional radio-resistance of tardigrades. The authors first characterized DNA damage and repair in the model tardigrade species Hypsibius exemplaris after exposure to ionizing radiation (IR). They found that tardigrades experience high levels of DNA single-strand breaks, comparable to human cells, suggesting DNA repair plays a major role in their radio-resistance.
Comparative transcriptomics across three tardigrade species revealed strong upregulation of numerous DNA repair genes in response to IR, including key players in double-strand break repair, single-strand break repair, and base excision repair pathways. Notably, a novel tardigrade-specific gene called Tardigrade DNA damage Response 1 (TDR1) was among the most strongly induced genes.
Further analyses showed that the TDR1 protein directly interacts with DNA and can form aggregates at high concentrations. When expressed in human cells, TDR1 improved resistance to the radiomimetic drug Bleomycin by reducing the number of DNA double-strand break markers (phospho-H2AX foci).
The authors propose that TDR1 is a novel tardigrade-specific DNA binding protein that contributes to radio-resistance, potentially by regulating chromosome organization to facilitate DNA repair. The study highlights the importance of DNA repair mechanisms in the exceptional resilience of tardigrades to ionizing radiation.

Stats

Tardigrades experience ~0.05-0.1 single-strand breaks per Mb per Gy of ionizing radiation, comparable to the rate in human cells.
Expression of TDR1-GFP from various tardigrade species reduced the number of phospho-H2AX foci in human U2OS cells treated with the radiomimetic drug Bleomycin.

Quotes

"Remarkably, the strongest upregulations, both at RNA and protein levels, were detected for proteins acting early in DNA repair in the different pathways involved: XRCC5/XRCC6 in NHEJ, POLQ in MMEJ, XRCC1 in SSB, and PARP2/PARP3 which act as DNA damage sensors common to all double-strand break repair pathways."
"Given that TDR1 can form aggregates with DNA in vitro, we speculate that it may favor DNA repair by regulating chromosomal organization."

Key Insights Distilled From

Comparative transcriptomics reveal a novel tardigrade specific DNA binding protein induced in response to ionizing radiation

by Anoud,M., De... at www.biorxiv.org 09-09-2023

https://www.biorxiv.org/content/10.1101/2023.09.08.556854v2

Deeper Inquiries

What other tardigrade-specific genes or mechanisms may contribute to their exceptional resistance to ionizing radiation?

Tardigrades exhibit exceptional resistance to ionizing radiation, and in addition to the TDR1 gene identified in the study, there are likely other tardigrade-specific genes and mechanisms that contribute to their radio-resistance. One such gene family is the AMNP gene family, which encodes Mn-Peroxidases that are overexpressed in response to desiccation and UVC in tardigrades. These proteins have been shown to increase tolerance to oxidative stress when expressed in human cells. Additionally, other novel tardigrade-specific genes involved in resistance to desiccation, such as CAHS, MAHS, and SAHS, may also play a role in radio-resistance. These genes are involved in protecting tardigrades from extreme environmental conditions and could potentially contribute to their ability to withstand ionizing radiation.

How do the DNA repair mechanisms in tardigrades differ from those in other radio-resistant organisms like rotifers and Deinococcus bacteria?

The DNA repair mechanisms in tardigrades, rotifers, and Deinococcus bacteria all play a crucial role in their radio-resistance, but there are some differences in how these organisms repair DNA damage. In tardigrades, the rate of single-strand breaks induced by ionizing radiation is roughly equivalent to that in human cells, suggesting that DNA repair plays a predominant role in their radio-resistance. Tardigrades upregulate a wide range of DNA repair genes, including those involved in double-strand break repair, base excision repair, and homologous recombination. This comprehensive response to DNA damage likely contributes to their ability to withstand high levels of radiation.
On the other hand, rotifers have been shown to have a rate of DNA double-strand breaks equivalent to that in human cells, indicating that DNA repair, rather than DNA protection, is the primary mechanism underlying their radio-resistance. Rotifers upregulate DNA repair genes in response to ionizing radiation, similar to tardigrades, suggesting a conserved strategy for coping with DNA damage. Deinococcus bacteria, such as Deinococcus radiodurans, are known for their highly efficient DNA repair mechanisms in response to high levels of DNA damage induced by radiation. These bacteria upregulate DNA repair genes and have specialized mechanisms for repairing DNA double-strand breaks, allowing them to survive extreme doses of radiation.

Could the insights into tardigrade DNA repair strategies provide inspiration for developing new approaches to enhance radiation tolerance in human cells or tissues?

The insights gained from studying tardigrade DNA repair strategies could indeed provide inspiration for developing new approaches to enhance radiation tolerance in human cells or tissues. Understanding the mechanisms by which tardigrades repair DNA damage and withstand high levels of ionizing radiation may lead to the identification of novel genes and pathways that could be targeted to enhance radiation tolerance in human cells. For example, the discovery of the TDR1 gene, a novel tardigrade-specific DNA binding protein involved in DNA repair, could inspire the development of therapeutic strategies to enhance DNA repair efficiency in human cells exposed to radiation.
By studying the unique adaptations of tardigrades to extreme environmental conditions, researchers may uncover new targets for intervention that could improve the resilience of human cells to radiation-induced DNA damage. This could have significant implications for cancer treatment, radiation therapy, and space exploration, where enhancing radiation tolerance in human tissues is a critical goal.