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New functions for an ancient domain

Nature Structural & Molecular Biology volume 16, pages 904–907 (2009)Cite this article

Macrodomains function as binding modules for metabolites of NAD+, including poly(ADP-ribose). Three new studies explore how binding of poly(ADP-ribose) by the macrodomains of histone variant macroH2A1.1 and the ATP-dependent chromatin-remodeling protein ALC1 (also called CHD1L) leads to the modulation of chromatin structure, regulating nuclear functions such as DNA-damage detection and repair.

Much of the research on the biology of PAR has focused on the synthesis of the polymer from ADPR units derived from donor NAD+ molecules, by enzymes such as PARP1 (refs. 6,7; Fig. 1a,b). PARP1, a ubiquitous and abundant nuclear protein, is the founding member of the PARP superfamily14, as well as the primary PAR producer and acceptor (through automodification) in cells15. It is a chromatin-associated protein that binds specifically to nucleosomes15 and localizes to the promoters of actively transcribed genes16. As such, PARP1 has key roles in a variety of nuclear functions, including DNA-damage detection and repair, modulation of chromatin structure and gene regulation7,17. Although less is known about the biology of PAR, studies over the past decade have begun to identify and characterize the proteins that bind to this rapidly synthesized and degraded polymer3,7,18,19,20. These studies have resulted in the identification of three conserved motifs or domains that bind PAR, including (i) a consensus motif of ∼20 amino acids that contains interspersed basic and hydrophobic amino acid residues19,20; (ii) PAR-binding zinc-finger motifs18,21; and (iii) macrodomains3,4,5. Many of the proteins containing these PAR binding motifs or domains are involved in the regulation of DNA repair and chromatin structure.

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Figure 1: Macrodomains bind metabolites of NAD+.
Figure 2: Macrodomain-containing proteins in humans.
Figure 3: Macrodomains are ancient and highly conserved structural domains that bind metabolites of NAD+.

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Acknowledgements

The author would like to thank C. Danko for assistance with the bioinformatics analysis of the macrodomain-containing proteins (Fig. 2), and N. Hah and J. Seckute for assistance with rendering the X-ray crystal structures (Fig. 3).

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  1. W. Lee Kraus is in the Department of Molecular Biology and Genetics, and the Department of Pharmacology, Cornell University, Ithaca, New York, USA, Weill Medical College of Cornell University, New York, New York, USA.,

    W Lee Kraus

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Kraus, W. New functions for an ancient domain. Nat Struct Mol Biol 16, 904–907 (2009). https://doi.org/10.1038/nsmb0909-904

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