title: Coordination of DNA repair by NEIL1 and PARP-1: a possible link to aging.
abstract: Oxidative DNA damage accumulates with age and is repaired primarily via the base excision repair (BER) pathway. This process is initiated by DNA glycosylases, which remove damaged bases in a substrate-specific manner. The DNA glycosylases human 8-oxoguanine-DNA glycosylase (OGG1) and NEIL1, a mammalian homolog ofEscherichia coli endonuclease VIII, have overlapping yet distinct substrate specificity. Recently, we reported that OGG1 binds to the Poly(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein that poly(ADP-ribosyl)ates nuclear proteins in response to DNA damage and other cellular signals. Here, we show that NEIL1 and PARP-1 bind both in vitro and in vivo. PARP-1 binds to the C-terminal-100 amino acids of NEIL1 and NEIL1 binds to the BRCT domain of PARP-1. NEIL1 stimulates the poly(ADP-ribosyl)ation activity of PARP-1. Furthermore, NEIL-deficient fibroblasts have impaired poly(ADP-ribosyl)ation of cellular proteins after DNA damage, which can be rescued by NEIL1 expression. Additionally, PARP-1 inhibits NEIL1 incision activity in a concentration-dependent manner. Consistent with the idea of impaired DNA repair during aging, we observed differential binding of PARP-1 to recombinant NEIL1 in older mice compared to younger mice. These data further support the idea that dynamic interplay between different base excision repair proteins is important for efficient BER.
authors.affiliation: Laboratory of Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Noren Hooten
authors.forename: Megan
authors.initials: M
authors.lastname: Fitzpatrick
authors.forename: Kari
authors.initials: K
authors.lastname: Kompaniez
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Jacob
authors.forename: Brittany R
authors.initials: BR
authors.lastname: Moore
authors.forename: Julia
authors.initials: J
authors.lastname: Nagle
authors.forename: Janice
authors.initials: J
authors.lastname: Barnes
authors.forename: Althaf
authors.initials: A
authors.lastname: Lohani
authors.forename: Michele K
authors.initials: MK
authors.lastname: Evans
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
chemical_list: C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D005982:Glutathione Transferase; D045647:DNA Glycosylases; C473634:NEIL1 protein, human; C481347:Neil1 protein, mouse