[Frontiers in Bioscience 14, 3246-3258, January 1, 2009]

Sensing NAD metabolites through macro domains

Susanne Till, Andreas G. Ladurner

European Molecular Biology Laboratory (EMBL), Gene Expression Unit, Structural and Computational Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Macro domains in bacteria and viruses
4. Macro domains and poly-ADP-ribosyl-polymerases (PARPs)
4.1. Macro-containing PAPRs
4.2. Interaction of macro domains with PARP1
5. Macro domains in histones
5.1. The histone variant macroH2A
5.2. Differential expression patterns of macroH2A isoforms
5.3. The histone macroH2A is enriched in the inactive X chromosome
5.4. MacroH2A- a marker for heterochromatic regions?
5.4.1. How does macroH2A influence heterochromatin formation?
5.4.2. MacroH2A and senescence-associated heterochromatin foci (SAHF)
5.4.3. Patterns of macroH2A chromatin deposition
5.5. The histone variant macroH2A1.1 .and its ligand ADP-ribose
6. Macro domains and sirtuins- direct and indirect links
6.1. Regulatory role of macro domains in Sir2-mediated catalysis
6.2. An active role of macro domains in Sir2 biology
6.3. Macro domains may buffer Sir2 catalysis
6.4. Conformational responses to Sir2 metabolites by macro domains
6.5. Auto-inhibitory events in proteins combining Sir2 and macro folds
7. Macro domains as a potential therapeutic target
8. Conclusions
9. Acknowledgments
10. References

1. ABSTRACT

The macro module is a globular protein domain of about 25 kDa that is evolutionarily conserved in organisms from viruses, bacteria, yeast to humans. It is generally part of proteins that have wide-ranging (and yet to be discovered) cellular functions. There are several examples of macro domains associated with modules showing homology to poly-ADP-ribosyl-polymerases. Many macro domains, including those of the human histone macroH2A1.1, bind NAD metabolites such as ADP-ribose, suggesting that macro domains may function in the recognition of this and related molecules. The presence of a metabolite-binding function in a repressive chromatin component opens new potential connections between chromosome structure, gene silencing and cellular metabolism. Current evidence suggests that macro domains also represent a novel tool for studying NAD metabolites and may be an attractive drug target for the treatment of diseases.