SIRT1/PARP1 crosstalk: connecting DNA damage and metabolism

Abstract

An intricate network regulates the activities of SIRT1 and PARP1 proteins and continues to be uncovered. Both SIRT1 and PARP1 share a common co-factor nicotinamide adenine dinucleotide (NAD+) and several common substrates, including regulators of DNA damage response and circadian rhythms. We review this complex network using an interactive Molecular Interaction Map (MIM) to explore the interplay between these two proteins. Here we discuss how NAD + competition and post-transcriptional/translational feedback mechanisms create a regulatory network sensitive to environmental cues, such as genotoxic stress and metabolic states, and examine the role of those interactions in DNA repair and ultimately, cell fate decisions.

Figure 1

SIRT1 and PARP1 Molecular Interaction Map. Blue: Post-translational modifications, Red: Inhibition and cleavage, Green: Stimulation and catalysis.

Figure 2

Modular layout diagram of SIRT1 and PARP1 MIM. Arrows connecting modules indicate that a node starting in a module connects to a node in the target module.

Figure 3

Reference guide for the MIM notation.

Figure 4

The effect of NMNAT1 binding on SIRT1 and PARP1 activity. Zhang et al. proposed that NMNAT1 may stimulate SIRT1 activity; indicated by the dashed line.

Figure 5

Interactions between SIRT1 and transcription factors c-MYC and E2F1. Solid lines between SIRT1 and c-MYC indicated are interactions from Yuan, Minter-Dykhouse et al. 2009 forming a negative feedback loop, while dashed lines are findings related to SIRT1 and c-MYC from Menssen, Hydbring et al. 2012.

Figure 6

Interactions of SIRT1 and PARP1 with circadian clock components.