AP endonuclease-independent DNA base excision repair in human cells.
The paradigm for repair of oxidized base lesions in genomes via the base excision repair (BER) pathway is based on studies in Escherichia coli, in which AP endonuclease (APE) removes all 3' blocking groups (including 3' phosphate) generated by DNA glycosylase/AP lyases after base excision. The recently discovered mammalian DNA glycosylase/AP lyases, NEIL1 and NEIL2, unlike the previously characterized OGG1 and NTH1, generate DNA strand breaks with 3' phosphate termini. Here we show that in mammalian cells, removal of the 3' phosphate is dependent on polynucleotide kinase (PNK), and not APE. NEIL1 stably interacts with other BER proteins, DNA polymerase beta (pol beta) and DNA ligase IIIalpha. The complex of NEIL1, pol beta, and DNA ligase IIIalpha together with PNK suggests coordination of NEIL1-initiated repair. That NEIL1/PNK could also repair the products of other DNA glycosylases suggests a broad role for this APE-independent BER pathway in mammals.
Wiederhold
Lee
L
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77555, USA.
Leppard
John B
JB
Kedar
Padmini
P
Karimi-Busheri
Feridoun
F
Rasouli-Nia
Aghdass
A
Weinfeld
Michael
M
Tomkinson
Alan E
AE
Izumi
Tadahide
T
Prasad
Rajendra
R
Wilson
Samuel H
SH
Mitra
Sankar
S
Hazra
Tapas K
TK
D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D045647:DNA Glycosylases / Q000378:metabolism*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D006801:Humans; D000075223:Poly-ADP-Ribose Binding Proteins; D011116:Polynucleotide 5'-Hydroxyl-Kinase / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D020798:Two-Hybrid System Techniques; D029867:Xenopus Proteins
D000075223:Poly-ADP-Ribose Binding Proteins; D029867:Xenopus Proteins; D004247:DNA; D011116:Polynucleotide 5'-Hydroxyl-Kinase; D019951:DNA Polymerase beta; D045647:DNA Glycosylases; C473634:NEIL1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus