Pediatric brain tumors: mutations of two dioxygenases (hABH2 and hABH3) that directly repair alkylation damage.
Alkylating agents, commonly used for brain tumor therapy, induce DNA and RNA lesions that, if not repaired, drive cells to apoptosis. Thus, cellular mechanisms that are responsible for nucleic acid repair are possibly involved in drug resistance. This work analyzes hABH2 and hABH3, two human Fe(II)-dependent dioxygenases in pediatric brain tumors that are treated with alkylating agents. We analyzed 25 brain tumor samples for hABH2 and hABH3 mutations; a subset of samples was tested for quantitative expression with Real-Time PCR. Sequencing analysis showed two new mutations in two glioma patients, one of hABH2 coding sequence (I141 V) and the other of hABH3 (D189 N). The mutation at codon 189 falls in a crucial region of the protein. All subjects analyzed by Real-Time PCR showed an enhanced expression of the two genes, particularly of hABH2. This is the first study of hABH2 and hABH3 in pediatric brain tumors; further molecular investigations of their mutations and expression may help determine their role in response to chemotherapy.
Cetica
Valentina
V
Onco-Hematology Unit, Department of Pediatrics, Florence Medical School, A. Meyer Children's Hospital, viale Pieraccini 24, 50139, Florence, Italy. v.cetica@meyer.it
Genitori
Lorenzo
L
Giunti
Laura
L
Sanzo
Massimiliano
M
Bernini
Gabriella
G
Massimino
Maura
M
Sardi
Iacopo
I
D000293:Adolescent; D000071499:AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; D000478:Alkylation; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D049308:Dioxygenases / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013125:Spinal Neoplasms / Q000235:genetics / Q000556:secondary
D012333:RNA, Messenger; D049308:Dioxygenases; C486439:ALKBH3 protein, human; D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; C486440:ALKBH2 protein, human; D000071499:AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; D045643:DNA Repair Enzymes