Ordered Cooperative Functions of PRMT1, p300, and CARM1 in Transcriptional Activation by p53

Abstract

Transcriptional coactivators that modify histones represent an increasingly important group of regulatory factors, although their ability to modify other factors as well precludes common assumptions that they necessarily act by histone modification. In an extension of previous studies showing a role for acetyltransferase p300/CBP in p53 function, we have used systems reconstituted with recombinant chromatin templates and (co)activators to demonstrate (1) the additional involvement of protein arginine methyltransferases PRMT1 and CARM1 in p53 function; (2) both independent and ordered cooperative functions of p300, PRMT1, and CARM1; and (3) mechanisms that involve direct interactions with p53 and, most importantly, obligatory modifications of corresponding histone substrates. ChIP analyses have confirmed the ordered accumulation of these (and other) coactivators and cognate histone modifications on the GADD45 gene following ectopic p53 expression and/or UV irradiation. These studies thus define diverse cofactor functions, as well as underlying mechanisms involving distinct histone modifications, in p53-dependent gene activation.

Crosstalk between site-specific modifications on p53 and histone H3

“…Histones have been shown to be essential substrates for p53-dependent methyl transferase activity, in particular CARM1 and PRMT1 are known to bind directly to p53. The work of An et al (2004) indicates a p53-dependent accumulation of distinct histone modifications in response to the activity of CARM1 and PRMT1. In the present study, mono-methylation at histone H3 K4 was elevated in cells expressing p53 while di-methylation at histone H3 K9 was abrogated (Figure 3), suggesting a role for p53 in histone H3 methylation at K4 and K9 which is not influenced by modifications of p53 at S15 or S37.…”

Transcriptional regulation by p53: one protein, many possibilities

“…The first one is built on the assumption that the promoter region of the gene to be activated by p53 is usually not accessible to the general transcription factors and RNA polymerase. In this scenario binding of p53 to its REs within a promoter would facilitate promoter opening via recruiting either chromatin remodeling factors (CRF) 91,92 (though see reference Hill et al 93 ) or histone transacetylases (HAT) [94][95][96][97] and/or methyltransferases 98 (Figure 2). This view has been validated recently in a significant number of studies.…”

“…49,55,[94][95][96][97] The involvement of PRMT1 and CARM1 methyltransferases in p53 function has been also demonstrated in the in vitro study utilizing a chromatin template with GADD45 p53 RE. 98 Thus, histone modifications and the subsequent alterations in chromatin structure and function seem to be one of the major outcomes of p53 binding to the RE. In addition, p53 has been shown to facilitate formation of preinitiation complex via direct interactions with the components of Mediator complex.…”

Interaction between p53 and estradiol pathways in transcriptional responses to chemotherapeutics

“…48,49 p53 and ER have been functionally and physically related to proteins involved in chromatin methyl mark changes, such as G9a and LSD1. [50][51][52][53][54][55] However, the outcome of the induced epigenetic changes is variable. For example, G9a, considered the major euchromatin H3K9 methyltransferase, can act both as corepressor and as a coactivator for nuclear receptor functions, in cooperation with CARM1 and p300.…”

“…50 Notably, both CARM1 and p300 can be recruited by p53 contributing to transcriptional activation. 51 Acetylation marks at H3 and H4 histone tails are considered chromatin activation markers. Both p53 and ER can recruit histone acetyltransferases contributing to gene activation.…”