Role of senataxin in DNA damage and telomeric stability.
Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia and oculomotor apraxia. The gene mutated in AOA2, SETX, encodes senataxin (SETX), a putative DNA/RNA helicase. The presence of the helicase domain led us to investigate whether SETX might play a role in DNA damage repair and telomere stability. We analyzed the response of AOA2 lymphocytes and lymphoblasts after treatment with camptothecin (CPT), mitomycin C (MMC), H₂O₂ and X-rays by cytogenetic and Q-FISH (quantitative-FISH) assays. The rate of chromosomal aberrations was normal in AOA2 cells after treatment with CPT, MMC, H₂O₂ and X-rays. Conversely, Q-FISH analysis showed constitutively reduced telomere length in AOA2 lymphocytes, compared to age-matched controls. Furthermore, CPT- or X-ray-induced telomere shortening was more marked in AOA2 than in control cells. The partial co-localization of SETX with telomeric DNA, demonstrated by combined immunofluorescence-Q-FISH and chromatin immunoprecipitation, suggests a possible involvement of SETX in telomere stability.
II School of Medicine, Department of Clinical and Molecular Medicine, University La Sapienza, Roma, Italy. andrea.deamicis@unirom
Andrea
A
De Amicis
Maria
M
Piane
Francesca
F
Ferrari
Maurizio
M
Fanciulli
Domenico
D
Delia
Luciana
L
Chessa
D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D004249:DNA Damage; D004265:DNA Helicases; D004260:DNA Repair; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017404:In Situ Hybridization, Fluorescence; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D016685:Mitomycin / Q000494:pharmacology; D064251:Multifunctional Enzymes; D020365:RNA Helicases / Q000235:genetics / Q000502:physiology*; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000201:enzymology / Q000235:genetics; D016615:Telomere / Q000201:enzymology / Q000235:genetics*; D014965:X-Rays
D064251:Multifunctional Enzymes; D016685:Mitomycin; D006861:Hydrogen Peroxide; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases; D002166:Camptothecin