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TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo
journal contribution
posted on 2023-06-08, 08:19 authored by Sachin Katyal, Sherif F El-Khamisy, Helen R Russell, Yang Liu, Limei Ju, Keith CaldecottKeith Caldecott, Peter J McKinnonDefective Tyrosyl-DNA phosphodiesterase 1 (TDP1) can cause spinocerebellar ataxia with axonal neuropathy (SCAN1), a neurodegenerative syndrome associated with marked cerebellar atrophy and peripheral neuropathy. Although SCAN1 lymphoblastoid cells show pronounced defects in the repair of chromosomal single-strand breaks (SSBs), it is unknown if this DNA repair activity is important for neurons or for preventing neurodegeneration. Therefore, we generated Tdp1-/- mice to assess the role of Tdp1 in the nervous system. Using both in vitro and in vivo assays, we found that cerebellar neurons or primary astrocytes derived from Tdp1-/- mice display an inability to rapidly repair DNA SSBs associated with Top1¿DNA complexes or oxidative damage. Moreover, loss of Tdp1 resulted in age-dependent and progressive cerebellar atrophy. Tdp1-/- mice treated with topotecan, a drug that increases levels of Top1¿DNA complexes, also demonstrated significant loss of intestinal and hematopoietic progenitor cells. These data indicate that TDP1 is required for neural homeostasis, and reveal a widespread requisite for TDP1 function in response to acutely elevated levels of Top1-associated DNA strand breaks.
History
Publication status
- Published
Journal
EMBO JournalISSN
0261-4189Publisher
Nature Publishing GroupExternal DOI
Volume
26Page range
4720-4731Pages
12.0Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Notes
I am co-correspondng author on this manuscript and my postdoc (El Khamisy) was co-first author.Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06Usage metrics
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