Histone poly ADP-ribosylation

Relationships between histone methylation and DNA methylation and histone acetyation and DNA methylation have been reported [191,314,315], A similar relationship may exist between poly(ADP ribosylated) HI and DNA methylation. Inhibition of poly(ADP-ribose) polymerase with 3-aminobenzamide increases the susceptibility of L929 mouse fibroblast nuclei to be methylated by endogenous DNA methyltransferases [316,317], Further, there is evidence that poly(ADP ribosylation) protects CpG islands located at the 5 end of housekeeping genes from methylation [318], Future studies will likely reveal an interesting dynamic relationship between histone methylation, histone acetylation, and histone poly(ADP-ribosylation). 

In order to determine the effect of core histone poly(ADP-ribosyl)ation on chromatin structure, we have incubated histone HI depleted chromatin with purified poly-(ADP-ribose) polymerase. This chromatin was then reconstituted with histone HI at a ratio of histone HI to DNA of 1. It was found that this chromatin did not recondense as the control chromatin did (A. Huletsky and G. de Murcia, unpublished observations). These results strongly suggest a close contact between histone H2B and histone HI and that modification of the N-terminal part of histone H2B, which was found to be poly(ADP-ribosyl)ated [32, 33], affects the integrity of the chromatin structure. In this process histone H2B would have an important role to play together with histone H1. 

To date, at least five biotinylation sites have been identified in histones H3 [lysine (K)-4, K9, K18 and probably K23] and H4 (K8, K12 and probably K16) (Camporeale et al. 2004 Kobza et al. 2005 Kobza et al. 2008). K9 and K13 in histone H2A might also be biotinylated (Chew et al. 2006), but the abundance of these two marks appears to be very low (Stanley et al. 2001). Studies with synthetic HLCS substrates provide unambiguous evidence that biotinylation of histones by HLCS is a substrate-specific process (Hassan et al. 2009a). Histone biotinylation is a comparably rare event (<0.1% of histones are biotinylated), but the abundance of an epigenetic mark is not necessarily a marker for its importance. For example, serine-14 phosphorylation in histone H2B and histone poly(ADP-ribosylation) are detectable only after induction of apoptosis... 

Krupitza G, Cerutti P (1989) Poly(ADP-ribosylation) of histones in intact human keratinocytes. Biochemistry 28 4054 060... 

Kun E, Kirsten E, Ordahl CP (2002) Coenzymatic activity of randomly broken or intact double-stranded DNAs in auto and histone HI trans-poly(ADP-ribosylation), catalyzed by poly(ADP-ribose) polymerase (PARP I). J Biol Chem 277 39066-39069 Kun E, Kirsten E, Mendeleyev J, Ordahl CP (2004) Regulation of the enzymatic catalysis of poly(ADP-ribose) polymerase by dsDNA, polyamines, Mg2-F, Ca2-F, histones HI and H3, and ATP. Biochemistry 43 210-216... 

Histone ADP-ribosylation was first reported in 1968 [290]. Poly(ADP-ribosylation) has been implicated in several nuclear processes, including DNA replication, repair and recombination [291-294]. Histone HI and the four core histones are modified by adenosine diphospho (ADP) ribosylation which involves the transfer of the ADP-ribose moiety of NAD" " to the histone acceptor (Figs. 1 and 2). HI is the principle poly(ADP-ribosylated) histone, while core histones are ADP-ribosylated to a minor extent [295-297]. HI is modified at Glu residues 2, 14 (or 15), and 116 (or 117) and at Lys located at the C-terminus [25,298,299]. Poly(ADP-ribosylated) HI is associated with dynamically acetylated core histones [295]. There is conflicting results as to whether poly(ADP-ribosylation) of HI promotes chromatin decondensation [300-304]. 

Realini and Althaus [313] have put forth the hypothesis that poly(ADP-ribosylation) may have a function in histone shuttling. They propose that poly(ADP-ribose) polymerase directed to sites of DNA strand breaks would auto-modify itself generating multiple ADP-ribose polymers. The polymers would lead to the dissociation of the histones from DNA onto the polymers. The DNA would now be free for processing (e.g., by enzymes involved in excision repair). The action of poly(ADP-ribose) glycohydrolase would degrade the... 

Fig. 6. Post-translational modifications of core and linker histones. The sites of acetylation, phosphorylation, poly-ADP ribosylation, methylation, and ubiquitination are incficated by numbers that correspond to the amino acid position from the N-termini of the molecules. The nomenclature of histone HI variants is as in Fig. 3. The length of C- and N-terminal tails is in relative scale between core histones to illustrate primary structural differences between these proteins.

Yet another hypothesis considers the somatic variant Hle of histone HI, in its poly(ADP-ribosyl)ated isoform, as a nuclear traw -acting factor involved in maintaining the methylation pattern on DNA [161]. 

Figure 5. Poly(ADP-ribosyl)ation-dependent histone shuttle on DNA. Step (1) shows a poly(ADP-ribose) polymerase molecule bound to chromatin. Step (2) auto(ADP-ri-bosyDation of the polymerase attracts histones from the DNA so they become noncovalently bound to the polymeric ADP-ribose chains attached to the polymerase. Step (3) indicates an extreme case where the local DNA has been completely denuded of histones. Step (4) upon degradation of the poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase the histones reassociate with the DNA. (From Realini and Althaus, 1992).

Although a precise definition of the role of nuclear poly(ADP-ribosyl)ation is not available, the histone-shuttle mechanism proposed by Althaus and colleagues offers a possible unifying explanation of numerous experimental findings. While this model will come under further experimental scrutiny, the effects of ADP-ribo-sylating individual chromosomal proteins other than the polymerase itself (automodification) still needs to be elucidated. 

Histones are also subject to reversible post-synthetic modifications, including phosphorylation, acetylation, and poly ADP-ribosylation. The functions of these modifications remain to be fully established, but there are good indications that ... 

PARP-1 is a signaling enzyme that transfers ADP-ribose groups from NAD to itself and other nuclear proteins in response to detecting DNA damage. Poly(ADP)ribosylation of histones has been shown to loosen chromatin (de Murcia et al, 1986), indicating that damage detection by PARP-1 leads to increased access to the site of damage for other repair... 

Realini CA, Althaus FR. Histone shuttling by poly(ADP-ribosylation). J Biol Chem 1992 267(26) 18858-65. 

From reconstitution experiments where either purified PARP-1 or PARP-2 were mixed with purified nuclei from PARP-1 deficient cells (Fig. 3D), it can be inferred that PARP-1 preferentially poly(ADP-ribosyl)ates the linker histone HI, whereas PARP-2 modifies preferentially the core histone H2B. Therefore, PARP-1 and PARP-2 have different targets both in DNA and in chromatin further indicating that, as chromatin modifiers, they play specific functions. 

Boulikas T. Poly(ADP-ribosylated) histones in chromatin replication. J Biol Chem 1990 265 14638-14647. 

Faraone-Mennella MR, De Lucia F, Gentile N et al. In vitro poly(ADP-ribosyl)ated histones Hla and Hit modulate rat testis chromatin differentially. J Cell Biochem 1999 76 20-29. 

As the in vivo introduction of new methyl groups on DNA involves the inhibition of poly(ADP-ribosyl)ation, which in turn can be correlated to a process of chromatin remodeling, parallel experiments were carried out, the only difference being that—for the in vitro reconsti-mtion of chromatin fibers—DNA sequences involved were either unmethylated or methylated with bacterial 5 I methyltransferase. The reconstitution of chromatin fibers was performed by adding either only the core histones or additionally H1 linker histone. 

Tikoo K, Lau SS, Monks TJ. Histone H3 phosphorylation is coupled to poly-(ADP-ribosylation) during reactive oxygen species-induced death in renal proximal tubular epithelial cells. Mol Pharmacol... 

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