PARPs and NAD+

Studies of poly(ADP-ribosyl)ation by nuclear poly(ADP-ribose) polymerases (PARPs) enzymes were largely focused on their roles in DNA damage detection and repair in the 1960s through 1990s. In the early 2000s, the Kraus Lab was one of a small number that began to link PARP-1, an abundant nuclear PARP, to the regulation of chromatin structure and gene regulation. Using a range of biophysical, biochemical, and molecular approaches, the Kraus Lab found that PARP-1 plays key roles in the modulation of chromatin structure and gene expression in response to extracellular signals, such as those mediated by estrogens and TNFα. In addition, we have taken the lead in trying to understand how the synthesis of nuclear NAD+, the substrate for PARP-1, by the nuclear NAD+ synthase NMNAT-1 controls the gene regulatory functions of PARP-1 and downstream biological outcomes. These studies have linked cellular metabolic state, especially in the nucleus, to signal-regulated transcriptional outcomes.

Selected Publications

Krishnakumar R., Gamble M. J., Frizzell K. M., Berrocal J. G., Kininis M., and Kraus W. L. (2008) Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes. Science. 319:819-821. PMID: 18258916

Gamble, M. J., Frizzell, K. M., Yang, C., Krishnakumar, R., & Kraus, W. L. (2010) The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing. Genes Dev. 24(1), 21-32. PMCID: PMC2802188

Krishnakumar R., Kraus W. L. (2010) PARP-1 Regulates chromatin structure and transcription through a KDM5B-dependent Pathway. Molecular Cell. 39:736-749. PMCID: PMC2939044

Gibson, B.A., Zhang, Y., Jiang, H., Hussey, K.M., Shrimp, J.H., Lin, H., Schwede, F., Yu, Y., and Kraus, W.L. (2016) Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation. Science. 353:45-50. PMID: 27256882

Liu, Z., Kraus W.L. (2017) Catalytic-independent functions of PARP-1 determine Sox2 pioneer activity at intractable genomic loci. Molecular Cell. 65: 589-603. PMID: 28212747

Luo, X., Ryu K.W., Kim D.-K., Nandu T., Medina C.J., Gupte R., Gibson B.A., Soccio R.E., Yu Y., Gupta R., Kraus W.L. (2017) PARP-1 controls the adipogenic transcription program by PARylating C/EPBβ and modulating its transcriptional activity. Molecular Cell. 65:260-271. PMID: 28107648

Ryu, K. W., Nandu, T., Kim, J., Challa, S., DeBerardinis, R. J., & Kraus, W. L. (2018) Metabolic regulation of transcription through compartmentalized NAD(+) biosynthesis. Science. 360(6389)