Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0004135 (
ATM
)
13,001
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Ataxia Telangiectasia
(
A-T
) is neurodegenerative syndrome caused by inherited mutations inactivating the
ATM
kinase, a master regulator of the DNA damage response (DDR). What makes neurons vulnerable to
ATM
loss remains unclear. In this study we assessed on human iPSC-derived neurons whether the abnormal accumulation of DNA-Topoisomerase 1 adducts (Top1ccs) found in
A-T
impairs transcription elongation, thus favoring neurodegeneration. Furthermore, whether neuronal activity-induced immediate early genes (IEGs), a process involving the formation of DNA breaks, is affected by
ATM
deficiency. We found that Top1cc trapping by CPT induces an
ATM
-dependent DDR as well as an
ATM
-independent induction of IEGs and repression especially of long genes. As revealed by nascent RNA sequencing, transcriptional elongation and recovery were found to proceed with the same rate, irrespective of gene length and
ATM
status. Neuronal activity induced by glutamate receptors stimulation, or membrane depolarization with KCl, triggered a DDR and expression of IEGs, the latter independent of
ATM
. In unperturbed
A-T
neurons a set of genes (FN1, DCN,
RASGRF1
, FZD1, EOMES, SHH, NR2E1) implicated in the development, maintenance and physiology of central nervous system was specifically downregulated, underscoring their potential involvement in the neurodegenerative process in
A-T
patients.
...
PMID:DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients. 3067 1
