Base excision DNA repair defect in Gadd45a-deficient cells.
As one of a number of p53-regulated genes, Gadd45a (growth arrest and DNA damage inducible gene) has been shown to delay carcinogenesis and decrease mutation frequency. Gadd45a is known to regulate nucleotide excision DNA repair (NER) in response to UV radiation. Here, we report an emerging role for Gadd45a in base excision repair (BER). Gadd45a-null mouse embryo fibroblasts MEF and gadd45a-deficient human colon cancer cells exhibited slow BER after treatment with methyl methanesulfonate (MMS) a pure base-damaging agent. In addition, removal of AP sites by apurinic/apyrimidinic endonuclease 1/redox factor 1 (APE1/Ref1) was significantly delayed in gadd45a-null cells. Moreover, the localization of APE1/Ref1 within the nucleus was observed in gadd45a wild-type cells, whereas APE1 become mainly distributed in the cytoplasm, and there is a reduced interaction with proliferating cell nuclear antigen (PCNA) in Gadd45a-deficient cells. Inasmuch as p53 has been shown to regulate BER in addition to the NER pathway, our data suggest that p53-regulated gene Gadd45a contributes to the BER response by affecting the interaction of cellular APE1/Ref1 with PCNA. Gadd45a might be a key component gene of the p53 pathway involved in protection from carcinogenic base damage and maintenance of genomic stability, although the downstream mechanism including APE1/Ref1 will need further study.
Jung
H J
HJ
Department of Pharmacology, Institute for Basic Medical Science (IBMS), School of Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, South Korea.
Kim
E H
EH
Mun
J-Y
JY
Park
S
S
Smith
M L
ML
Han
S S
SS
Seo
Y R
YR
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D005347:Fibroblasts; D006801:Humans; D008741:Methyl Methanesulfonate / Q000633:toxicity; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000502:physiology; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D008741:Methyl Methanesulfonate; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; C439070:GADD45A protein, human; D000097642:GADD45 Proteins