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Gmeiner et al. Cancer Drug Resist 2021;4:758-61 https://dx.doi.org/10.20517/cdr.2021.65 Page 760

field anticipated that nature developed a “solution” to the formation of the potentially toxic Top1cc or
Top2cc. Scientists proposed an enzyme that was able to hydrolyze the phosphodiester linkage formed
between the topoisomerases active site tyrosine and the end of a DNA strand. It was not until 1996 when
[9]
Yang et al. from the NIH reported this hallmark enzyme activity with the discovery of Tyrosyl-DNA
phosphodiesterase I (Tdp1) in yeast. The review of Brettrager and van Waardenburg in this issue focuses
[10]
on Tdp1 and its potential as an anti-cancer target. Brettrager and van Waardenburg highlight the Tdp1
[10]
catalytic mechanism to remove Top1 from its covalent complex with the DNA. Removal of Top1 from its
Top1-DNA complex occurs via a transient Tdp1-DNA covalent complex (Tdp1cc) thus forming a potential
toxic enzyme-DNA adduct itself. Currently two different approaches are developed to use this surprising
Achilles’ heel in the fight against cancer. The first one is to inhibit Tdp1 enzyme activity, thus preventing
Tdp1 from removing the drug stabilized Top1cc or Top2cc. Small molecule Tdp1 inhibitors are being
developed by various groups throughout the world as discussed in this review. A second potential approach
to target Tdp1 for the treatment of cancer was emphasized with the discovery that dysregulation of Tdp1
catalytic mechanism via the substitution of one of the two Tdp1 catalytic histidines to an arginine is the
molecular basis for the rare autosomal neurodegenerative disease, SCAN1. This mutation of the general
acid/base His to Arg resulted in an increased half-life of Tdp1cc that is detrimental for cerebellar cells. This
suggests that identification of small molecules that stabilize the Tdp1cc similar to the Top1 and Top2
poisons would offer a novel therapeutic strategy in the fight against cancer.

Over the last 50 years, we have gained a wealth of knowledge on maintenance of DNA topology by DNA
topoisomerases, and how we can use their mechanism of action to treat human disease, specifically cancer.
In this special issue, recent highlights in our understanding of DNA topoisomerase I and II biology, use of
topoisomerase-targeting therapeutics, and the mechanism of repair of enzyme-DNA reaction intermediates
are summarized. Although, topoisomerase-targeting therapeutics are highly successful in the clinic, novel
therapeutic approaches are urgently needed to circumvent drug-resistance mechanisms and to treat
additional cancer types. Moreover, development of small molecules to target DNA topoisomerase III would
complement and expand the current anti-cancer treatment options directed at topoisomerases. As such, it is
clear that there is much more knowledge to be gained to understand the role of DNA topoisomerases in
human disease and more effectively treat cancer patients and overcome resistance to anti-cancer drugs.

DECLARATIONS
Authors’ contributions
Wrote and edited this editorial: Gmeiner WH, van Waardenburg RCAM

Availability of data and materials
Not applicable.

Financial support and sponsorship
van Waardenburg RCAM in part funded by American Cancer Society UAB ACS-IRG Junior Faculty
Development Grant (ACS-IRG-60-001-53), Department of Defense OCRP pilot award W81XWH-15-1-
0198, and the National Institutes of Health Cancer Center Core Support Grant (P30CA013148) and
National Institutes of Health - National Institute of Disorders and Stroke (1R21NS116312-01A1).
Gmeiner WH in part supported by the National Cancer Institute Cancer Center Support Grant
(P30CA012197) issued to the Wake Forest Baptist Comprehensive Cancer Center and National Institutes of
Health -National Cancer Institute R21 CA218933.