Journal
EMBO JOURNAL
Volume 26, Issue 22, Pages 4720-4731Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7601869
Keywords
dNA repair; neurodegeneration; single-strand; breaks; TDP1; topoisomerase 1
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Funding
- Medical Research Council [G0400959, G0300662B, G0001259] Funding Source: researchfish
- MRC [G0001259, G0400959] Funding Source: UKRI
- Medical Research Council [G0001259, G0400959] Funding Source: Medline
- NCI NIH HHS [P30 CA21765, P30 CA021765, CA-21765] Funding Source: Medline
- NINDS NIH HHS [R56 NS037956, NS-37956, R01 NS037956] Funding Source: Medline
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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.
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