Differential modulation of base excision repair activities during brain ontogeny: implications for repair of transcribed DNA.
DNA repair sustains fidelity of genomic replication in proliferating cells and integrity of transcribed sequences in postmitotic tissues. The repair process is critical in the brain, because high oxygen consumption exacerbates the risk for accumulation of oxidative DNA lesions in postmitotic neurons. Most oxidative DNA damage is repaired by the base excision repair (BER) pathway, which is initiated by specialized DNA glycosylases. Because the newly discovered Nei-like mammalian DNA glycosylases (NEIL1/2) proficiently excise oxidized bases from bubble structured DNA, it was suggested that NEILs favor repair of transcribed or replicated DNA. In addition, since NEILs generate 3'-phosphate termini, which are poor targets for AP endonuclease (APE1), it was proposed that APE1-dependent and independent BER sub-pathways exist in mammalian cells. We measured expression and activities of BER enzymes during brain ontogeny, i.e., during a physiologic transition from proliferative to postmitotic differentiated state. While a subset of BER enzymes, exhibited declining expression and excision activities, expression of NEIL1 and NEIL2 glycosylases increased during brain development. Furthermore, the capacity for excision of 5-hydroxyuracil from bubble structured DNA was retained in the mature rat brain suggesting a role for NEIL glycosylases in maintaining the integrity of transcribed DNA in postmitotic brain.
Englander
Ella W
EW
Department of Surgery, The University of Texas Medical Branch, Shriners Hospitals for Children, 815 Market Street, Galveston, TX 77550, USA. elenglan@utmb.edu
Ma
Huaxian
H
D000375:Aging / Q000502:physiology; D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics*; D005786:Gene Expression Regulation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000235:genetics*
D012333:RNA, Messenger; D004247:DNA