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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 McKinnon
Defective 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 Journal

ISSN

0261-4189

Publisher

Nature Publishing Group

Volume

26

Page range

4720-4731

Pages

12.0

Department 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

2012-02-06

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