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 of Escherichia 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.

Multitasking Roles for Poly(ADP-ribosyl)ation in Aging and Longevity

“…Similarly, PARP1 binds to the glycosylase NEIL1 which stimulates PARylation activity, whereas activated PARP1 inhibits incision activity of NEIL1. Interestingly, and consistent with the notion of compromised DNA repair during aging, PARP1 binds less efficiently to NEIL1 in old mice compared to young ones [94]. Another, important factor in BER/SSBR is the loading platform X-ray repair complementing factor 1 (XRCC1).…”

Hypersensitivity of mouse NEIL1-knockdown cells to hydrogen peroxide during S phase

“…Interaction of hNEIL1 with poly (ADP-ribose) polymerase-1 (PARP-1) [27], a DNA damage sensor, has been observed in vitro and in vivo , and interaction of the C-terminal region of hNEIL1 and the BRCT domain of PARP1 inhibits hNEIL1 incision activity in a concentration-dependent manner. These results suggest that hNEIL1 is not a simple glycosylase/AP-lyase, but plays multiple roles in a highly organized DNA damage control system.…”

NAD and the aging process: Role in life, death and everything in between

“…For example, one of the current hypotheses to explain the age-related NAD decline is that this phenomenon could be mediated by accumulation of DNA damage and activation of PARP1 during aging (Figure 4) (Imai and Guarente, 2014). However, depending on the study, it has been observed that levels and activity of PARPs may either decrease or increase during chronological aging or accelerated aging disorders (Bakondi et al, 2011; Braidy et al, 2011; Noren Hooten et al, 2012; Scheibye-Knudsen et al, 2014; Zhang et al, 2014). For example, it was reported that in Cockayne syndrome (CS), an accelerated aging disorder characterized by progressive neurodegeneration, there is aberrant PARP activation leading to decreased SIRT1 activity and mitochondrial dysfunction (Scheibye-Knudsen et al, 2014).…”