Diversity within the prb pathway: is there a code of conduct?

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1 REVIEW : is there a code of conduct? S Munro, SM Carr and NB La Thangue (2012) 31, & 2012 Macmillan ublishers Limited All rights reserved /12 Laboratory of Cancer Biology, Department of Oncology, dical Sciences Division, University of Oxford, Oxford, UK The failure of cell proliferation to be properly regulated is a hallmark of tumourigenesis. The retinoblastoma protein () pathway represents a key component in the regulation of the cell cycle and tumour suppression. Recent findings have revealed new levels of complexity reflecting a repertoire of post-translational modifications that occur on together with its key effector. Here we provide an overview of the modifications and consider the possibility of a code that endows with the ability to function in diverse physiological settings. (2012) 31, ; doi: /onc ; published online 16 January 2012 Keywords: ; ; phosphorylation; acetylation; methylation Introduction The regulation of the G1 to S phase transition during the cell cycle is essential for correctly controlled cell proliferation. One of the key players in this process is the retinoblastoma protein (). is a tumour suppressor protein that is absent or functionally inactivated in at least a third of all human tumours (Weinberg, 1995). One of the ways in which has an essential role in proliferation control is through binding to and regulating its key effector, the E2F family of transcription factors. The E2F family coordinates the transcription of genes that are required for cell cycle progression. When bound to, E2F-mediated transcriptional activity is reduced and cell cycle progression is prevented (Dyson, 1998; Trimarchi and Lees, 2002; Stevens and La Thangue, 2003). The E2F family comprises eight family members (-8) with different subunits exhibiting distinct activities with regard to cell cycle progression and apoptosis (Stevens and La Thangue, 2003). With the exception of two family members (E2F-7 and E2F-8), E2F activity arises from the interaction of E2F with a D binding partner, to form a transcriptionally active heterodimeric complex (Trimarchi and Lees, 2002). For the purposes of this review we will focus on the most Correspondence: rofessor NB La Thangue, Laboratory of Cancer Biology, Department of Oncology, dical Sciences Division, University of Oxford, Old Road Campus Research Building, Old Road Campus, off Roosevelt Drive, Oxford OX3 7DQ, UK. nick.lathangue@clinpharm.ox.ac.uk Received 19 August 2011; accepted 23 November 2011; published online 16 January 2012 extensively investigated family member,. Significantly, represents a paradox as it can act as both a tumour suppressor and an oncogene, and depending on the cellular signals transmitted, has the ability to stimulate proliferation or apoptosis (Stevens and La Thangue, 2003; olager and Ginsberg, 2008). This dual function necessitates that activity is tightly regulated during the cell cycle, which is accomplished in a variety of ways. For example, can upregulate its own transcription, its activity is modulated by interacting proteins, protein turnover is tightly controlled and is regulated by post-translational modifications (Dyson, 1998; Harbour and Dean, 2000; Stevens and La Thangue, 2003). One of the most well-understood aspects of E2F regulation is the inactivation of its transcriptional activity via the interaction with. The inhibition of activity, which occurs as a consequence of this interaction, coincides with the ability of to arrest cells in G1 (Harbour and Dean, 2000). During the cell cycle, as cells progress from the G1 to S phase, the sequential phosphorylation of by cyclin/cyclindependant kinase (Cdk) complexes causes the release of and the activation of genes required for the entry into S phase (Sherr, 2000; Classon and Harlow, 2002; Longworth and Dyson, 2010). belongs to a family of proteins referred to as pocket proteins, which also includes the related proteins, p107 and p130 (Cobrinik, 2005). These proteins are defined by a conserved pocket domain which serves as a binding site for numerous cellular proteins and viral oncoproteins (Cobrinik, 2005). In addition to its wellestablished role in cell cycle progression, studies in Rb / mice highlighted an essential function for in other cellular processes, such as differentiation and apoptosis (Clarke et al., 1992; Jacks et al., 1992). In addition to binding and preventing its transcriptional activity, can also actively repress transcription through targeting chromatin-remodelling enzymes, such as histone deacetylases and methyltransferases, and interact with chromatin-associated proteins to influence the chromatin environment (Longworth and Dyson, 2010). The observation that interacts with a wide range of chromatin-binding proteins and chromatin-modifying enzymes has led to the concept that can exert global control upon chromatin, a notion which is strengthened by the fact that cells lacking family members display altered chromatin states and exhibit chromosomal aberrations (Herrera et al., 1996; Gonzalo et al., 2005).

2 4344 SMunroet al The regulation of the /E2F pathway by cyclin/ Cdk phosphorylation is intrinsic to cell cycle control. Cyclin/Cdk complexes are themselves negatively regulated by Cdk inhibitors such as p16 INK4A, p21 CI1 and p27 KI1 (Sherr and Roberts, 2004). Whilst phosphorylation is recognized as a post-translational modification that significantly influences activity, it is now apparent that other types of modification can also impact upon /E2F. For example, and are modified on lysine residues by post-translational modifications such as acetylation, methylation, ubiquitination and SUMOylation. Most of our knowledge of lysine acetylation and methylation has come from the studies on histones in chromatin control (Zhang and Reinberg, 2001). The diversity and extent to which histones can be modified has led to the concept of the histone code (Jenuwein and Allis, 2001). The histone code suggests that the modification of histone tails is written by one set of enzymes, read by effector molecules and erased by another set of enzymes (Jenuwein and Allis, 2001). It is believed that chromatin control by readers, writers and erasers enables fine-tuning in response to different physiological contexts. In simple terms, some posttranslational modifications are associated with transcriptional activation and others with repression, which is facilitated by recruiting reader proteins, which then direct gene activity. Furthermore, additional levels of complexity exist as single residues can be targeted by more that one type of modification. Most significantly, the concept of post-translational modifications creating a code that can impart different biological activities may not be restricted to histones (Sims and Reinberg, 2008). The p53 tumour suppressor protein is a particularly good example, where many of the enzymes that act upon histones also target p53. Thus, p53 can be modified by phosphorylation, acetylation, methylation, SUMOylation and NEDDylation (ek and Anderson, 2009). It is also clear that there is cross-talk between p53 modifications, where different combinations of modification can promote diverse outcomes (ek and Anderson, 2009; Dai and Gu, 2010). Recent evidence suggests that and are subjected to additional levels of post-translational control by phosphorylation, acetylation, methylation, SUMOylation and ubiquitination. Here, we will discuss advances in our understanding of the increasingly wide spectrum of post-translational modifications that act upon and, raising the possibility that a code exists which provides greater levels of complexity on, enabling it to function in diverse physiological roles. phosphorylation is a nuclear phosphoprotein, and the phosphorylation of on many sites by the cyclin/cdks has been extensively documented (Mittnacht, 1998; Adams, 2001). harbours up to 16 potential Cdk consensus sites (Knudsen and Wang, 1996) (Figure 1). As cells progress through the cell cycle, is gradually phosphorylated by different combinations of cyclin/ Cdk complexes. The increase in the level of phosphorylation results in the dissociation from S249 T356 T373 S567 S612 K720 S795 S807 S811 S821 S826 K873 K874 S Ac Ac A B pocket region K810 K860 K873 Ub phosphorylation Ac acetylation S31 Ac Ac Ac K117 K120 K125 K185 S332 S337 S364 S403 S433 S Ub methylation SUMOylation ubiquitination cyclin A binding DNA binding dimerization marked box transactivation/ binding Figure 1 Schematic representation of and post-translational modifications. The location of post-translational modifications in and is shown. The A and B domains, which comprise the pocket, are indicated. K, lysine; S, serine; T, threonine.

3 S Munro et al, allowing to activate the transcription of genes required for DNA synthesis and cell cycle progression (Connell-Crowley et al., 1997; Mittnacht, 1998; Sherr, 2000). It is believed that in early G1, cyclin D/Cdk4/6 phosphorylates targeting S249, T356, S807, S811 and T826 (Zarkowska and Mittnacht, 1997); cyclin E/ Cdk2 targets in late G 1 and early S phase phosphorylating S612 and T821. Inactive, hyperphosphorylated is maintained by cyclin A/Cdk2 throughout the S phase and the rest of the cell cycle. The initial phosphorylation events occur in the C-terminal region and cause a conformational change in, allowing an intramolecular interaction to occur with the central pocket region (Rubin et al., 2005); this interaction excludes HDAC binding to the pocket and thus prevents active transcriptional repression. The conformational changes that occur as a result of early phosphorylation events on collectively lead to the interaction of with cyclin E/Cdk2, which phosphorylates S567. As S567 is located in the core of the pocket region, phosphorylation of this residue prevents from binding to and inactivating (Harbour et al., 1999). During mitotic exit, is dephosphorylated by protein phosphatase 1 (1) (Ludlow et al., 1993). A structural study examining the association between and 1 revealed an enzyme docking site in the C- terminal domain of that is essential for 1 activity towards (Hirschi et al., 2010). The phosphatase binding site maps to amino acid residues , which overlaps with a well-documented Cdk binding site (amino acid ) (Schulman et al., 1998; Adams et al., 1999; Lowe et al., 2002). 1 competes with Cdkcyclins for binding, maintains in an active growth-suppressing form and blocks cell cycle progression (Hirschi et al., 2010). is also phosphorylated by a number of other protein kinases. For example, there have been reports that is phosphorylated by p38 MA kinase (Wang et al., 1999; Nath et al., 2003; Yeste-Velasco et al., 2009). p38 is a stress-activated protein kinase which phosphorylates on S567 (Delston et al., 2011). Under conditions of DNA damage, p38 phosphorylates Rb, which then allows to be targeted for degradation by Mdm2. Once is degraded, is released and activates the genes required for apoptosis (Delston et al., 2011). A wide variety of DNA-damaging agents can induce the phosphorylation of at S612 (Inoue et al., 2007). This phosphorylation event is mediated by either checkpoint kinase, Chk1 or Chk2, reflecting the type of DNA damage. hosphorylation events on are normally associated with the inactivation of and release of ; however, phosphorylation at S612 in response to DNA damage appears to represent an activating event. Indeed, S612 phosphorylation promotes the interaction between and, and is required for anti-apoptotic activity during the DNA damage response (Inoue et al., 2007). We do not have a complete understanding of the importance of individual residues and whether combinations of phosphorylation events result in particular outcomes. It is a widely accepted notion that inactivation of requires its sequential phosphorylation by cyclin/cdk complexes, although a number of studies suggest that this mechanism may not necessarily be general and widespread. A recent study adopting a more complex mutagenic approach found that phosphorylation of a single residue in the N-terminal region of was capable of causing inactivation (Lents et al., 2006; Gorges et al., 2008). A mutational analysis in which each Cdk phosphorylation site was restored individually revealed T373 as a critical residue involved in inactivation. Interestingly, it was also observed that the presence of the extreme C-terminal region of was required for this phosphorylation event. Acetylation of A further level of regulation on is mediated by the targeted acetylation of lysine residues (Figure 1). The p300 transcriptional co-activator acetylates on the adjacent lysine residues K873/K874 (Chan et al., 2001a), and acetylation is enhanced by the viral oncoprotein E1A, which recruits p300 and into a multimeric protein complex. Acetylation of impedes the phosphorylation of by cyclin/cdk complexes, which is perhaps not entirely unexpected as the site of acetylation falls within the motif believed to be required for binding Cdks (residues ) (Adams et al., 1999; Lowe et al., 2002). Acetylation of at K873/K874 is under cell cycle control and increased levels of acetylation occur during S phase (Chan et al., 2001a). has an essential and widespread role in differentiation (Clarke et al., 1992; Jacks et al., 1992; Gu et al., 1993). For example, the role of is well established in myogenesis, osteogenesis, adipogenesis and neurogenesis (Khidr and Chen, 2006). Elevated levels of acetylated are observed during differentiation (Chan et al., 2001a; Nguyen et al., 2004; ickard et al., 2010). Acetylated increases during myogenesis where the increase in acetylation coincides with hypophosphorylation (Nguyen et al., 2004). Like p300, the p300-associated factor (/CAF) is also required for differentiation (uri et al., 1997), and a role for /CAF as a potential histone acetyltransferase during differentiation has been suggested. Through its pocket region, interacts with the histone acetyltransferase domain of /CAF and during differentiation the interaction is enhanced. Acetylated cooperates with the transcription factor MyoD in achieving permanent growth arrest (Nguyen et al., 2004). It has been suggested that regulates MyoD activity by binding to and sequestering proteins that inhibit MyoD activity, such as the E1A-like inhibitor of differentiation (EID-1). During terminal differentiation, EID-1 forms a trimeric complex with and Mdm2. Mdm2 mediates the ubiquitination and degradation of EID-1, which in turn relieves repression exerted upon MyoD, allowing the activation of genes required for differentiation (MacLellan et al., 2000; Miyake et al., 2000). Signifi- 4345

4 4346 SMunroet al cantly, acetylated exhibits increased affinity for Mdm2, and by recruiting Mdm2 to the complex, acetylated promotes the degradation of EID-1, which ultimately leads to cell cycle exit and the transcription of genes required for differentiation (Chan et al., 2001a; Nguyen et al., 2004). During the DNA damage response, undergoes increased acetylation at K873/K874 (Markham et al., 2006). Treatment of cells with etoposide triggers a temporal induction in levels of acetylated. In addition to the pocket-dependant interaction with, harbours a second interaction domain, which is situated in the C-terminal domain of (Dick and Dyson, 2003). DNA damage-dependant acetylation of releases from the C-terminal interaction domain (Markham et al., 2006), which is a separate interface to the pocket-dependant interaction. The importance of this regulatory mechanism has yet to be established, but a possibility is that it has a part in -dependant apoptosis that occurs in response to DNA damage, perhaps facilitating the regulation of genes required for apoptosis. Tip60, a member of the MYST histone acetyltransferase family, can also acetylate. The lysine residues targeted by Tip60 remain to be identified, but as the mutant derivative K873/K874 could still be acetylated, it seems that the residues targeted by Tip60 are distinct from those acetylated by p300 and /CAF (Leduc et al., 2006). Tip60 interacts with and this triggers its degradation by the proteasome (Leduc et al., 2006). Further, through an unknown mechanism the tumour suppressor protein, p14 ARF prevents Tip60 acetylation of and in turn prevents its degradation (Leduc et al., 2006). A recent study in which the scope of lysine acetylation at the proteome-wide level was examined revealed further sites of acetylation on at K427, K548, K640, K653 and K896 (Choudhary et al., 2009). The functional relevance of these events awaits further investigation, but given that four of these residues are located in the vicinity of the pocket region of it is possible that they could affect interactions with proteins that bind to the pocket, with wide ranging consequences. It is interesting to note that the acetylation of lysine residues can create binding sites for proteins harbouring the protein module known as the bromodomain (Yang, 2004). It is therefore tempting to speculate that acetylated could perhaps recruit a bromodomain-containing protein; moreover, the binding of such a reader protein could potentially influence the downstream response. Lysine acetylation is a reversible process. SIRT1 (sirtuin 1) can interact with and deacetylate (Wong and Weber, 2007). SIRT1 is the human homologue of yeast silent information regulator 2; it is a class III HDAC subunit and its activity is regulated by the cofactor NAD þ. SIRT1 deacetylates a number of residues on histone proteins and more recently has been shown to deacetylate a wide range of non-histone proteins, including p53, p73, androgen receptor and Foxo proteins (Fang and Nicholl, 2011). SIRT1 interacts with and the related pocket proteins, p107 and p130 (Wong and Weber, 2007). A marked reduction in acetylation was observed when SIRT1 was introduced into cells at increasing levels, and omission of NAD þ failed to reduce acetylation (Wong and Weber, 2007), suggesting that SIRT1 can act as an eraser to remove the acetylation signals present on. methylation The regulation of protein function by methylation has been an area of intense interest in recent years. thylation by methyltransferases can occur on both lysine and arginine residues. A large number of methyltransferases have been identified, which can loosely be divided into two subgroups; lysine methyltransferases, mostly belonging to the SET domain family (Martin and Zhang, 2005), and arginine methyltransferase, referred to as protein arginine dimethyltransferases (Bedford and Clarke, 2009). Very interestingly, is methylated by the mono-methyltransferase Set7/9 at two distinct lysine residues within the C-terminal domain of, K873 and K810 (Munro et al., 2010; Carr et al., 2011) (Figure 1). thylation of at K873 creates a binding site for the heterochromatin protein, H1. H1 is involved with gene silencing and transcriptional inactivity (Fischle et al., 2003; Hediger and Gasser, 2006), and indeed when methylation of is prevented an increase in the expression of E2F target genes such as DHFR, Cdc6 and occurs (Munro et al., 2010). In addition, methylation at K873 can influence cell cycle progression; a mutant-derivative lacking methylation at K873 displayed reduced ability to cause cell cycle arrest when compared with the wild-type counterpart. These results indicate that methylation at K873 enhances activity, which in turn causes cell cycle arrest. Further, is an important player in the induction of cellular senescence and differentiation, which is tightly linked to its role as a tumour suppressor (Templeton et al., 1991). Derivatives of compromised in methylation were less efficient at inducing senescence and differentiation in cells compared with wild-type (Chan et al., 2001a; Nguyen et al., 2004), and the depletion of Set7/9 resulted in a reduced ability of cells to differentiate. Taken together, these results are suggestive of a role for methylation in regulating cell fate, and identify Set7/9 as a writer and H1 as a reader in regulating the properties of. The interplay between different types of post-translational modification in is nicely illustrated by recent reports on lysine methylation at K810. K810 lies within a Cdk consensus motif and is flanked by S807 and S811, and methylation of K810 prevents phosphorylation of the juxtapositioned sites (Carr et al., 2011) (Figure 1). During the DNA damage response, is predominantly hypophosphorylated (Knudsen et al., 2000). Consequently, it was hypothesized that this scenario might influence methylation at K810. When cells were

5 treated with DNA-damaging agents, the anticipated decrease in phosphorylation of contrasted with the increased methylation at K810. A mutant derivative of, which could not be methylated at K810, exhibited reduced DNA binding to E2F-regulated promoters and furthermore failed to cause cell cycle arrest (Carr et al., 2011). Structural modelling suggested that methylation at K810 would physically preclude the interaction between and Cdks, explaining the reduced level of Cdk-dependant phosphorylation. Interestingly, the effects of K810 methylation were not restricted to just S807 and S811, as methylation of K810 appeared to affect global phosphorylation of, influencing phosphorylation of distant sites located in the N-terminal region of, such as S249 and T252. The mechanism underlying the impact that methylation at K810 has on the global phosphorylation of remains to be determined. However, it is feasible that phosphorylation of S807/S811 is a priming event that is a prerequisite for subsequent phosphorylation events on at distant Cdk phoshorylation sites. Equally, it is possible that methylation at K810 introduces a site for a reader protein, the binding of which excludes access of Cdk to distal phosphorylation sites. The direct methylation of K810 thus provides an additional level through which phosphorylation can be regulated, and an example of the interplay that can occur between different levels of control (Figure 2). SMYD2 is a Set domain-containing protein first identified as a H3K36 dimethyltransferase (Brown et al., 2006). SMYD2 possesses growth-suppressing properties and exists in complex with Sin3A and HDAC (Brown et al., 2006). SMYD2 mono-methylates on K860 S Munro et al during cell cycle exit, differentiation and during DNA damage (Saddic et al., 2010). In a similar manner to the methylation at K873 and K810, methylation of K860 by the writer SMYD2 caused a reduction in the expression of E2F target genes. Mono-methylation at K860 creates a binding site for L3MBTL1, a histone methyl-binding protein capable of condensing chromatin and repressing gene expression (Bonasio et al., 2010). L3MTL1 contains three MBT domains that bind to mono- and dimethylated lysine residues (Min et al., 2007). thylation of K860 by SMYD2 is read by L3MBTL1, which augments growth regulation (Saddic et al., 2010). Given that the location of K860 is very close to the Cdk docking site, it is conceivable that its methylation could also hinder phosphorylation of. Other post-translational modifications Lysine residues can be modified by the covalent attachment of ubiquitin and ubiquitin-like proteins (ickart and Eddins, 2004). Mdm2 is a member of the RING finger family of E3 ligases, which by binding to E2 ubiquitin-conjugating enzymes promotes the ubiquitination of target proteins. Mdm2 has previously been shown to interact with (Xiao et al., 1995) and ubiquitinate in vivo (Uchida et al., 2005). The location of ubiquitination has yet to be defined, although the evidence suggests that it is located within the C-terminal region (Uchida et al., 2005). Ubiquitination by Mdm2 facilitates degradation via the ubiquitin-proteasome pathway (Uchida et al., 2005). As loss of is associated with uncontrolled cell 4347 normal growth conditions DNA damage p21 Cdk/cyclin Set7/9 K810 cell cycle genes cell cycle genes transcription on transcription off cell cycle progression cell cycle arrest Figure 2 Model depicting the interplay between methylation (K810) and phosphorylation. Cdk phosphorylation of relieves cell cycle arrest by facilitating the expression of E2F target genes. Under conditions of DNA damage, methylation of by Set7/9 retains in a hypophosphorylated growth-arresting state by hindering Cdk phosphorylation, which in turn prevents the expression of E2F target genes and prompts cell cycle arrest.

6 4348 SMunroet al proliferation and oncogenesis it was perhaps not surprising that an inverse relationship between Mdm2 and was observed in lung cancer biopsies; high levels of Mdm2 correlated with low levels of, arguing that Mdm2 may influence in lung cancer in situ (Uchida et al., 2005). As ubiquitination occurs in the C-terminal region of, which is heavily modified by other post-translational modifications (Figure 1), it is possible that interplay exists between ubiquitination and other modifications such as phosphorylation, acetylation and methylation. SUMO (small ubiquitin-related modifier) is a reversible post-translational modification, and many of its protein targets include transcriptional regulators (Muller et al., 2001, 2004; Wilkinson and Henley, 2010). is SUMOylated in the B domain of the pocket region on K720 (Ledl et al., 2005) (Figure 1), within a cluster of lysine residues that are essential for the interaction with LXCXE motif-containing proteins (Chan et al., 2001b). SUMOylation is regulated by the interaction of with certain LXCXE-motif containing proteins, including EID-1 and the viral oncoproteins E1A and HV E7, which bind to via LxCxE motifs and prevent SUMOylation (Ledl et al., 2005). SUMOylation preferentially occurs on hypophosphorylated, and may disrupt the / interaction (Ledl et al., 2005). Regulation of activity by phosphorylation hosphorylation of can also influence the / interaction, and in this respect several phosphorylation events on have been identified. is phosphorylated on S332 and S337, which prevent its interaction with (Fagan et al., 1994; Sahin and Sladek, 2010). p38 MA kinase targets S403 and S433, and this is important for export from the nucleus and subsequent degradation (Ivanova et al., 2009). Whilst E2F activity is positively regulated indirectly by cyclin D and cyclin E through their action upon, is also under negative regulation by cyclina/ Cdk2, and as cells enter S phase, binds to cyclina/cdk2, allowing the phosphorylation of D-1 and inhibition of E2F binding ability (Xu et al., 1994). It has been shown that DNA damage-responsive kinases can phosphorylate. Several studies found that protein levels are induced in response to DNA damage (Blattner et al., 1999; Lin et al., 2001; Stevens et al., 2003). is phosphorylated on S31 by ataxia telangiectasia mutated/ataxia telangiectasia and Rad3-related (ATM/ATR) kinases (Lin et al., 2001). A yeast two hybrid screen in which a small N-terminal region of (containing S31) was used as the bait isolated TopB1 (DNA topoisomerase IIb binding protein 1) as a protein that could interact with (Liu et al., 2003). TopB1 contains eight BRCT motifs and it is through the sixth motif that it forms an interaction with, an association which is induced by DNA damage and dependant upon phosphorylation of S31 (Liu et al., 2003). Many activities are downregulated upon its association with TopB1, including transcription, induction of S phase and apoptosis (Liu et al., 2003). chanistically, it is believed that the recruitment of Brg1/Brm (a subunit of the SWI/SNF chromatin-remodelling complex) to the TopB1/ complex leads to the repression of E2F- 1 regulated promoters (Liu et al., 2004). The functional significance of phosphorylation events in is well illustrated by studies on proteins. The family member, t specifically binds to phosphorylated S31 (Wang et al., 2004). In this regard, binding to during DNA damage promotes stabilization by inhibition of ubiquitination, which is required for the expression of apoptotic target genes and doxorubicin-induced apoptosis (Wang et al., 2004). In another study, levels were found to increase in response to etoposide and UV treatment in cells. A key component of the DNA-damage signalling pathway, Chk2, was identified as the kinase responsible for phosphorylating at S364, resulting in increased protein stability and apoptosis (Stevens et al., 2003). acetylation is acetylated by the histone acetyltransferases p300 and /CAF (Trouche et al., 1996; Martinez-Balbas et al., 2000; Marzio et al., 2000). Acetylation of enhances DNA binding ability, transcriptional activity and protein stability (Martinez-Balbas et al., 2000; Marzio et al., 2000). The residues acetylated by /CAF and p300 lie close to the DNA binding domain (Figure 1). Given the enhanced DNA binding activity, it is possible that acetylation influences the structure of to facilitate contact with DNA. Acetylation of is induced by DNA-damaging agents, and treatment of cells with chemotherapeutic agents like doxorubicin induce acetylation (ediconi et al., 2003). A mutated protein that mimicked acetylation showed much higher apoptotic activity than the wildtype protein, perhaps reflecting its ability to bind and activate the genes required for apoptosis (ediconi et al., 2003). Ubiquitination of The regulation of protein stability is central to control, and many of the modifications that target are known to influence turnover. is stabilized by DNA damage-dependant phosphorylation and acetylation events, which is believed to inhibit degradation mediated by the ubiquitin proteasome pathway (Lin et al., 2001; ediconi et al., 2003; Stevens et al., 2003). As cells progress from S phase into G2, undergoes rapid degradation mediated by the F-box-containing protein p45 SK2, which is the cell cycle-regulated component of the ubiquitin-protein ligase SCF SK2 (Jackson and Eldridge, 2002). Upon completion of S phase, Skp2 binds to the N-terminal region of and targets it for degrada-

7 tion by the 26S proteasome (Marti et al., 1999). However, the interaction of with certain proteins can impact on its ubiquitination and degradation. For example, interacts with p14 ARF, which upregulates ubiquitination and promotes its degradation (Martelli et al., 2001). The Mdm2 protein has a surprising role in the regulation of ubiquitination; it binds to, increasing its half-life by displacing p45 SK2 (Zhang et al., 2005). Interestingly, although a negative regulator of, binding to protects from ubiquitination and subsequent degradation (Campanero and Flemington, 1997). Overall, therefore, ubiquitination appears to be regulated on several levels. The theme that emerges implies that a balance exists between different modifications and interacting proteins that determine protein stability. thylation of S Munro et al The histone methyltransferase Set7/9 methylates (Kontaki and Talianidis, 2010). Set7/9 methylates at K185, which although located within the DNA binding domain of, does not affect DNA binding activity in in vitro assays. There appears to be considerable interplay between methylation and other post-translational modifications; for example, methylation of antagonizes the acetylation and phosphorylation events that are required for its stabilization during the damage response, and methylation triggers ubiquitination and subsequent degradation of (Kontaki and Talianidis, 2010). thylation of is reduced upon DNA damage, where the demethylation event is likely to be mediated by the lysine-specific demethylase, LSD1, which reinstates apoptotic activity (Kontaki and Talianidis, 2010). Given the interplay with ubiquitination, it is possible that methylation of acts as a pivotal mechanism to maintain levels at an appropriate level for normal cell cycle progression. Under conditions such as DNA damage, removal of the methyl mark and subsequent phosphorylation or acetylation events stabilize, allowing the transcription of apoptotic genes. Conclusions The broad range of post-translational modifications that occur on and suggests that parallels can be drawn with the modifications of histone tails, whereby a particular modification either acting alone or in concert contributes to a code, which thereafter imparts a function on the protein (Jenuwein and Allis, 2001; Sims and Reinberg, 2008). Many of the enzymes that have previously been shown to act upon histone tails also modify and (Tables 1 and 2). As the chromatin modifications that these writers impart on histones direct transcriptional activity, it is possible that similar modifications of / act in an analogous fashion, to impose different consequences on the / E2F pathway. Several of the modifications on / described to date occur in response to genotoxic stress and therefore it is worth considering the potential interplay that may occur between the different types of events under DNA damage. Thus, is phosphorylated by DNA damage-responsive kinases (Lin et al., 2001; ediconi et al., 2003; Stevens et al., 2003). Although formal proof is lacking, it seems very likely that interplay will occur under these conditions. It is tempting to speculate that the extent of DNA damage is reflected in the degree to which is modified. For example, phosphorylation of S31 might recruit TopB1 and halt S phase progression, allowing DNA repair to take place. On the other hand, if the extent of DNA damage is too extreme to repair, phosphorylation together with acetylation might prompt the transcriptional activation of apoptotic genes (Figure 3). In addition, is methylated at K810 in response to DNA damage, which antagonizes its phosphorylation. erhaps during DNA damage, methylated turns off the expression of genes required for cell cycle progres Table 1 Summary of the post-translational modifications occurring on Site Modification Enzyme responsible Functional consequence S249 hosphorylation Cdk Transcription T356 hosphorylation Cdk Transcription T373 hosphorylation Cdk Transcription S567 hosphorylation p38 Cdk degradation Transcription S612 hosphorylation Chk1/Chk2 Cdk Increased binding to Transcription K720 SUMOylation Ubc9 Inhibits repression towards E2F S795 hosphorylation Cdk Transcription S807 hosphorylation Cdk Transcription K810 thylation Set7/9 Antagonizes phosphorylation S811 hosphorylation Cdk Transcription T821 hosphorylation Cdk Transcription T826 hosphorylation Cdk Transcription K860 thylation Smyd2 Augments repression K873 Acetylation thylation p300, /CAF Set7/9 revents phosphorylation, promotes differentiation Augments repression K874 Acetylation p300, /CAF revents phosphorylation, promotes differentiation

8 4350 SMunroet al Table 2 Summary of the post-translational modifications occurring on Amino acid Enzyme responsible Modification Functional consequence S31 ATM hosphorylation Increased protein stability, increased apoptosis K117 K120 K125 /CAF, p300 Acetylation Increased DNA binding, transcriptional activation of apoptotic target genes, increased protein stability K185 Set7/9 thylation Ubiquinitation and degradation of S332 S337 Cdk1 hosphorylation Can not bind to, therefore increased transcriptional activity S364 Chk2 hosphorylation Increased protein stability, increased apoptosis S403 p38 hosphorylation Nuclear export and degradation DNA damage 1 Demethylase(s)? LSD1 Sirt1 HDAC erasers Cdk/cyclin Set7/9 SMYD2 p300 /CAF ATM Chk2 writers? K810 L3MBTL1 K860 K873 H1 TopB Ac? Brd Ac Ac readers transcriptional activation (cell cycle genes) Cell cycle progression transcriptional repression Cell cycle arrest Differentiation Senescence transcription activation (apoptotic genes) Apoptosis Figure 3 Differential regulation of / by post-translational modifications. Three scenarios are shown that result in different outcomes for the cell; cell cycle progression, cell cycle arrest and apoptosis. The enzymes regulating these events are shown; namely writers (blue) and erasers (orange). When is methylated, it is envisaged that the binding of readers (red), including H1 and L3MBTL1, allow to repress the transcription of target genes, thus permitting cell cycle arrest, differentiation and senescence. Ac: acetylation;, methylation;, phosphorylation. sion, while the modifications that occur on initiate an apoptotic response (Figure 3). ost-translational modifications can hinder or assist the occurrence of other post-translational modifications. In the case of, methylation at K185 prevents phosphorylation and acetylation, and promotes ubiquitination (Kontaki and Talianidis, 2010). Likewise, when is targeted by methylation and acetylation, phosphorylation is reduced. Further, methylated lysine residues can serve as docking sites for reader effector proteins such as H1 and L3MBTL1, which have both been shown to bind to methylated and augment repression activity (Munro et al., 2010; Saddic et al., 2010) (Figure 3). It is becoming increasingly clear that a variety of nonhistone proteins are regulated by a code that dictates an important level of control that enables information beyond the primary amino acid sequence to be imparted on the biological activity of a protein. ost-translational modifications acting in concert with reader proteins on are likely to coordinate protein function in such a manner that imparts diversity on its biological activity. As the /E2F pathway has an integral role in many physiological processes, we can be confident that the range of post-translational modifications that have been documented to date are likely to reflect an increasingly complex repertoire of modifications that allow the pathway to orchestrate its extensive biological cues. Conflict of interest The authors declare no conflict of interest. Acknowledgements This work was supported by grants from CRUK, MRC, LRF, EU and AICR.

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