Details:

Alternative Title:
J Neurol Neuromedicine
Personal Author:
van Waardenburg, Robert C.A.M.
Description:
Tyrosyl-DNA phosphodiesterase I (TDP1), like most DNA repair associated proteins, is not essential for cell viability. However, dysfunctioning TDP1 or ATM (ataxia telangiectasia mutated) results in autosomal recessive neuropathology with similar phenotypes, including cerebellar atrophy. Dual inactivation of TDP1 and ATM causes synthetic lethality. A TDP1H|R catalytic mutant is associated with spinocerebellar ataxia with axonal neuropathy (SCAN1), and stabilizes the TDP1 catalytic obligatory enzyme-DNA covalent complex. The ATM kinase activates proteins early on in response to DNA damage. Tdp1-/- and Atm-/- mice exhibit accumulation of DNA topoisomerase I-DNA covalent complexes (TOPO1-cc) explicitly in neuronal tissue during development. TDP1 resolves 3'- and 5'-DNA adducts including trapped TOPO1-cc and TOPO1 protease resistant peptide-DNA complex. ATM appears to regulate the response to TOPO1-cc via a noncanonical function by regulating SUMO/ubiquitin-mediated TOPO1 degradation. In conclusion, TDP1 and ATM are critical factors for neuronal cell viability via two independent but cooperative pathways.
Subject:
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Article
Source:
J Neurol Neuromedicine. 1(5):25-29
Pubmed ID:
27747316
Pubmed Central ID:
PMC5064944
Document Type:
Journal Article
Funding:
K08 CA131483/CA/NCI NIH HHSUnited States/ ; P30 CA013148/CA/NCI NIH HHSUnited States/ ; R00 CA131489/CA/NCI NIH HHSUnited States/ ; U58 SO000004/SO/PHSPO CDC HHSUnited States/
K08 CA131483/CA/NCI NIH HHSUnited States/ ; P30 CA013148/CA/NCI NIH HHSUnited States/ ; R00 CA131489/CA/NCI NIH HHSUnited States/ ; U58 SO000004/SO/PHSPO CDC HHSUnited States/ Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:48872564f5005e6834ace186466590a63dbb2bd21cf514341c883e60d8b39db5
Download URL:
https://stacks.cdc.gov/view/cdc/42192/cdc_42192_DS1.pdf
File Type:

Supporting Files

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