Base excision repair dysfunction in a subgroup of patients with myelodysplastic syndrome.
In myelodysplastic syndromes (MDS) increased chromosomal breaks point toward defects in DNA repair machinery including base excision repair (BER) pathway involved in handling of oxidative DNA damage. We investigated whether defects in this pathway can be found in MDS. Elevated levels of 8-oxoguanine (8-OG) were found in a significant proportion of MDS patients, indicating increased oxidative DNA damage or defective handling of oxidative load. In a distinct subgroup of patients, increased 8-OG content was associated with increased hOGG1 mRNA expression and activity. In some patients, increased numbers of abasic sites (AP sites) correlated with low levels of POLbeta. To further investigate the nature of this defect, we examined genetic lesions potentially explaining accumulation of 8-OG and AP sites. We genotyped a large cohort of MDS patients and found a correlation between increased oxidative damage and the presence of the hOGG1-Cys326 allele suggesting inadequate compensatory feedback. Overall, this hOGG1 variant was more frequent in MDS, particularly in advanced forms, as compared to controls. In summary, we demonstrated that BER dysfunction in some MDS patients may be responsible for the increased 8-OG incorporation and explains one aspect of the propensity to chromosomal breaks in MDS but other mechanisms may also be involved.
Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
A M
AM
Jankowska
L P
LP
Gondek
H
H
Szpurka
Z P
ZP
Nearman
R V
RV
Tiu
J P
JP
Maciejewski
D000368:Aged; D000483:Alleles; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D002460:Cell Line / Q000378:metabolism; D019457:Chromosome Breakage; D015331:Cohort Studies; D004249:DNA Damage; D045647:DNA Glycosylases / Q000032:analysis / Q000235:genetics; D019951:DNA Polymerase beta / Q000032:analysis; D004260:DNA Repair; D004790:Enzyme Induction; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000097:blood; D006801:Humans; D007962:Leukocytes / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D017354:Point Mutation
C024829:8-hydroxyguanine; D006147:Guanine; D019951:DNA Polymerase beta; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human