1. Introduction
DNA replication, the basis of biological inheritance, is a fundamental process occurring during the S-phase of the cell cycle in all eukaryotes. In the nucleus, DNA is associated with histones, basic proteins that help package the lengthy genome to form nucleoprotein filaments called chromatin. Histones are essential for viability as they pack DNA into the nucleus and regulate access to the genetic information contained within the DNA. Due to their strong positive charge, non-chromatin-bound histones can bind non-specifically to negatively charged molecules in the cell, including nucleic acids such as DNA and RNA, as well as negatively charged proteins. Therefore, histone levels are tightly regulated to prevent harmful effects of free histone accumulation: this regulation takes place transcriptionally, posttranscriptionally, translationally and posttranslationally (reviewed in Gunjan et al., 2005). Despite this regulation, different situations can induce an accumulation of non-chromatin-bound histones, called “free” or “excess” histones (Gunjan & Verreault, 2003). In the budding yeast
A delicate balance between histone and DNA synthesis during the package of the genome into chromatin is essential for cell viability. For this reason, a key regulatory event during the G1/S transition is the induction of histone genes, which allows the coupling of bulk histone synthesis to ongoing DNA replication. In proliferating cells, the synthesis of the vast majority of histones occurs during the S-phase of the cell cycle (Osley, 1991). Moreover in recent years, a novel surveillance mechanism has been described in budding yeast that monitors the accumulation of non-chromatin-bound histones and promotes their rapid degradation by the proteasome in a Rad53 kinase-dependent manner (Gunjan & Verrault, 2003).
In this chapter, we will focus on the model yeast
2. DNA replication: a crucial event integrated in the cell cycle
DNA replication takes place during the S-phase of the cell cycle. To transmit genetic information over generations, DNA must be precisely replicated before chromosomal segregation takes place. For this purpose, the eukaryotic cell has regulatory mechanisms to limit chromosomal DNA duplication to once per cell cycle, to decide the onset of a new round of DNA replication and to respond to situations in which the genome is at risk.
2.1. Early events in chromosome replication
Accurate and complete DNA replication in each cell cycle and repair of DNA lesions are critical for the maintenance of genetic stability (Aguilera & Gomez-Gonzalez, 2008; Branzei & Foiani, 2008). Failures in this process reduce cell survival and lead to cancer and other diseases in higher metazoans (Hoeijmakers, 2001; Friedberg, 2003). Chromosomal DNA replication in eukaryotes initiates from multiple specific regions of chromosome DNA, known as origins of replication. Therefore, it is crucial to understand how each individual origin is regulated during the cell cycle.
In the budding yeast
In order to coordinate these processes, a regulatory link between DNA replication and cell cycle progression must exist. Firstly, faithful inheritance of the genetic material requires DNA replication to be precisely controlled so that it occurs once per cell cycle. If not, the pre-RC would be reassembled at origins that have already fired, resulting in an over-replication of some parts of the genome. The key to this regulation lies in the initiation of DNA replication and regulatory cell cycle elements control during the M/G1 and G1/S transitions. CDKs play an important role in separating these two reactions (Arias & Walter, 2007). During the mitotic exit and G1, CDK activity is reduced by two different mechanisms: down-regulation in the level of these cyclins and accumulation of the CDK inhibitor Sic1 (Stegmeier & Amon, 2004). Under these conditions, the pre-RCs are assembled at replication origins, but initiation does not occur because CDK activity is low. In the following S phase, S-CDK is activated and DNA replication initiates. At the same time, and very importantly, reassembly of the pre-RC at origins is blocked by CDK to inhibit re-replication (Diffley, 2004; Tanaka et al., 2007): CDK can phosphorylate all the pre-RC components, ORC, Cdc6, Cdt1, and Mcm2-7, to down-regulate their activities for the pre-RC formation (reviewed in Tanaka & Araki, 2010). Less is known, however, about the dephosphorylation of initiation proteins, whether it is necessary for replication origin resetting and the acting phosphatase(s) that might control this process and, therefore, replication licensing. Recently it has been demonstrated that Cdc14p resets the competency of replication licensing by dephosphorylating multiple initiation proteins during the mitotic exit in budding yeast (Zhai et al., 2010).
2.2. The importance of the G1/S transition
In
There are three G1 cyclins in
Cells tightly regulate the different cell cycle transitions to ensure the correct transmission of genetic information. Checkpoints are surveillance mechanisms that prevent one cell cycle stage from starting if a previous cell cycle stage has not been successfully completed. Checkpoints can be considered as signal transduction cascades with three components: sensors to detect incomplete or aberrant cell cycle events; transducers of the checkpoint signal; and targets that are modified by transducers to cause cell cycle arrest (Elledge, 1996). As the G1-to S phase transition (START) signifies a commitment to complete cell division, eukaryotic cells are capable of undergoing transient arrest during the G1/S transition if conditions which would be unfavourable for cell division, such as nutrient limitation (Gallego et al., 1997), environmental toxins (Philpott et al., 1998) or damaged DNA, are encountered. Impaired ability to either initiate the arrest or to subsequently recover from the arrest and to resume cell division appears to be detrimental (Hartwell & Kastan, 1994; Lydall & Weinert, 1995; Shaulian et al., 2000). In recent years, the way different DNA-damage situations can trigger cell cycle checkpoint machinery has been studied in great detail. DNA damage or replicative stress, depending on where the cell happens to be in the cell cycle, can cause cell cycle arrest via the “G1/S” checkpoint, the “intra-S” checkpoint or the “G2/M” checkpoint (Jares et al., 2000; Segurado & Tercero, 2009).
2.3. The “intra-S-phase” checkpoint response
The DNA-damage signalling pathway is highly conserved throughout eukaryotes (Lydall & Weinert, 1996). Under DNA damage situations, kinase Mec1 in
Another relevant response to cope with situations where the genome is at risk, owing to DNA damage or replicative stress, takes place during DNA replication, this being the so-called S-phase or replication checkpoint pathway (also called “intra-S-phase”, which refers to cells that have already passed START and begun replication) (Nyberg et al., 2002; Osborn et al., 2002; Paulovich & Hartwell, 1995; Segurado & Tercero, 2009). Two central players in this checkpoint in budding yeast are the aforementioned kinases Mec1 and Rad53. They are homologues of Rad3 and Cds1, respectively, in the fission yeast
In budding yeast, the signalling cascade triggered under replication stress culminates with the phosphorylation of Rad53 (Branzei & Foiani, 2009). This kinase is essential for the activation of the molecular mechanisms required to cope with replication arrest: (1) it promotes the stabilisation of stalled replication forks and allows DNA replication restart after removal of the blocking agent (Santocanale & Diffley, 1998; Tercero & Diffley, 2001); (2) it is also responsible for inducing the transcription factors of ribonucleotide reductase genes or DNA damage response genes (Allen et al., 1994; Huang et al., 1998; Zhao et al., 2001); (3) finally, Rad53 prevents the firing of late replication origins (Duch et al., 2011; Zegerman & Diffley, 2010) and restrains spindle elongation, thus preventing mitosis (Allen et al., 1994; Bachant et al., 2005; Weinert et al., 1994). Kinase Cdc7/Dbf4 is a target of the intra-S-phase checkpoint (Jares et al., 2000).
3. Replicating chromatin: DNA is associated with histones
The DNA of eukaryotic cells fits the confines of the nucleus by a hierarchical scheme of folding and compaction into chromatin. Nucleosomes, the repeating structural units of chromatin, consist in an octameric histone core comprising two copies each of H2A, H2B, H3 and H4, around which 147 bp of DNA are wrapped in 1.65 superhelical turns (Andrews & Luger, 2011; Luger et al., 1997). A linker or H1 histone molecule then associates with the nucleosome core particle (Brown, 2003). Thus nucleosomes are formed into regularly spaced arrays along DNA and can be mobilised by different ATP-dependent remodelling complexes, such as SWI/SNF or RSC, or ATP-independent ones, like the FACT complex. Histones are essential for viability as they pack DNA into the nucleus and regulate access to the genetic information contained within it.
The chromatin structure plays a central role in gene regulation and other nuclear processes, including DNA replication (Groth et al., 2007). During replication, the cell must replicate not only its DNA, but also its chromatin. Accordingly, another regulatory process during the G1/S transition is the induction of histone genes, which allows the coupling of bulk histone synthesis with ongoing DNA replication. In proliferating cells, the synthesis of the vast majority of histones occurs during the S-phase of the cell cycle. Inhibition of DNA synthesis results in a rapid repression of histone genes, indicating that it is tightly coupled with DNA replication.
An interesting question underlying this close coupling between DNA replication and histones expression is:
4. Avoiding free histones in yeast: controlling histones levels
To prevent deleterious effects of free histone accumulation, histone proteins are regulated transcriptionally, posttranscriptionally, translationally and posttranslationally (reviewed in Gunjan et al., 2005).
4.1. Transcriptional regulation
Cells must replicate not only their DNA during the S-phase, but also their chromatin. Accordingly, the transcription of histone genes is activated at the beginning of the S-phase to provide sufficient core histones to assemble replicated DNA. Correspondingly, inhibition of DNA synthesis results in a rapid repression of histone genes, indicating that it is tightly coupled with DNA replication (Osley, 1991; Breeden, 2003; reviewed in Gunjan et al., 2005).
The major core histone genes in
Three of the four divergent histone gene promoters (the two gene pairs that encode H3/H4, and
4.2. Posttranscriptional regulation
The increase in histone mRNAs during the S-phase is not only due to a cell cycle-regulated promoter in histone genes, but also to a regulated stability of histone messengers: histone mRNAs accumulate in the S-phase and are rapidly degraded as cells progress to the G2 phase of the cell cycle. This regulation mode is better understood in higher eukaryotes (Marzluff & Duronio, 2002), although the mechanisms to modulate the stability of histone RNAs differ among eukaryotic organisms. In
4.3. Controlling histone protein levels by proteolysis
In recent years, a novel mechanism to prevent the accumulation of free histones, which is superimposed upon the regulation of histone gene transcription and mRNA stability, has been described in budding yeast (Gunjan & Verreault, 2003; reviewed in Gunjan et al., 2006). The authors demonstrated that Rad53, but not Mec1, is required for the degradation of the excess histones that are not packaged into chromatin. Consequently,
5. Generating free histones during the cell cycle
So far we have discussed how cells tightly regulate histone levels to prevent harmful effects of free histones from binding non-specifically to nucleic acids and from interfering with processes that require access to genetic information. Firstly, delicate transcriptional and posttranscriptional regulations of histone genes, coupled with DNA replication during the S-phase of the cell cycle, efficiently avoid an accumulation of non-chromatin-bound histones. This kind of mechanisms is evolutionarily conserved (Osley, 1991; Marzluff & Duronio, 2002). Secondly, despite this regulation, situations where free histones appear exist and a posttranslational mechanism mediated by Rad53 induces the proteolysis of excess histones. Finally, therefore, it is interesting to wonder about the processes generating excess histones during the cell cycle (reviewed in Singh et al., 2009).
Firstly, it has been well-established that all eukaryotes have multiple genes encoding each histone protein. Histones are primarily synthesised in the S-phase and deposited by chromatin assembly factors or histone chaperones on replicating DNA to form chromatin in a process known as chromatin assembly (Gunjan et al., 2005). Different hypotheses have attempted to explain why eukaryotic cells carry such a large number of histone genes. The most simple explanation seems to be that the high demand of histones for chromatin assembly on newly replicated DNA can only be achieved by multiple histone genes. However, it has been shown that
Secondly, rigorously coupling histone synthesis with DNA replication (Stein & Stein, 1984) ensures the rapid incorporation of histones into newly synthesised DNA to form chromatin. However, different situations can generate DNA replication slow down or arrest, resulting in an accumulation of unincorporated newly synthesised histones (Bonner et al., 1988). To better illustrate these situations, replication inhibitors bring about a drastic drop in DNA synthesis and chromatin assembly. Moreover, DNA damage results in DNA replication slowing down or stalling, which is due to either the physical impediment posed by DNA lesions or, more likely, the activation of the intra-S-phase DNA damage checkpoint that prevents new origins from firing (Paulovich & Hartwell, 1995; Tercero & Diffley, 2001).
A third source of excess histones (non-chromatin-bound ones) may be those histones removed during DNA damage, repair and recombination. When DNA damage occurs in the chromatin context, repair factors have to gain access to the damaged site to carry out necessary repairs. In this sense, there is evidence suggesting that histones may be evicted locally from a DNA double strand break (DSB) site to allow access to the repair machinery (Tsukuda et al., 2005). A minor contribution of this last process to free histone accumulation may be expected.
6. A novel source of excess free histones: evicted from transcription
DNA is tightly packed into chromatin. Nucleosomes need to be disassembled and reassembled to allow efficient transcription by RNA polymerases. There are many different factors relating to this process. One very well described essential factor involved in RNA pol II transcription is the FACT complex (reviewed by Reinberg & Sims, 2006; Formosa, 2008). This complex is the only factor known to date that stimulates RNA Pol II-dependent transcription elongation through chromatin in a highly purified system (Orphanides et al., 1998; Pavri et al., 2006) and also
Our group, in collaboration with the labs of Geli and Gunjan, has recently demonstrated that a dysfunction in chromatin reassembly during active Pol II transcription through defects on the Spt16 protein can generate an accumulation of free histones. We have shown that a strong genetic interaction takes place between the
Beyond the S-phase, transcribed chromatin is probably the main source of free histones in yeast cells, presumably due to the minor imbalances between histone supply and demand during chromatin reassembly. Our results indicate a novel and important role for FACT in yeast, that of a protective factor against the toxic risk represented by evicted histones. This model agrees with a recent publication which reports how Spt16 promotes the redeposition of the original H3 and H4 histones evicted by elongating Pol II (Jamai et al., 2009). The protective role against evicted histones is probably not an exclusive function of FACT, but a function of the other factors that cooperate during chromatin reassembly, like Spt6, for which we have also provided some evidence (Morillo-Huesca et al., 2010).
7. A novel signal regulating the G1/S transition: free histone levels
Our work has allowed us to propose that a dysfunction of chromatin reassembly factors, like FACT and Spt6, generates an accumulation of the excess histones evicted from transcription. In addition to this, we have found an interesting connection between free histone levels and cell cycle defects in the G1/S transition. We postulate that free or non-chromatin-bound histones can trigger the down-regulation of
In mammalian cells, histone overexpression slows down entry into and progression through the S-phase (Groth et al., 2007). Interestingly, depletion of human Spt16 leads to the repression of H1, H2A and H2B genes (Li et al., 2007), which could be the result of the accumulation of the free histones in human cells after FACT dysfunction. Given the analogy between the G1-S regulators in yeast (Cln3-SBF-Whi5-Rpd3) and mammals (CyclinD1-E2F-Rb-HDAC1) (Wang et al., 2009; Takahata et al., 2009), the functional link between the accumulation of free histones and the regulation of the G1-S transition may be evolutionarily conserved.
This chapter emphasises that excess free histones may have serious implications for the normal progression of DNA replication when the toxicity of free histones is maximal in the S-phase (Gunjan & Verreault, 2003). According to this scenario, a G1 delay in response to excess histones favours cell viability. In our model, represented in Figure 2, the G1 delay should allow cells to reduce the free histones levels through the Rad53/Tom1-mediated histone degradation pathway before entering the S-phase. It is interesting to note that Rad53 participates in different linked functions, such as the DNA damage checkpoint, the excess histone degradation pathway, and at the initiation of DNA replication. A model has been recently proposed in which Rad53 acts as a “nucleosome buffer” by interacting with origins of replication to prevent excess histones from binding to origins and to maintain a proper chromatin configuration (Holzen & Sclafani, 2010). For this reason, we propose the term
8. Conclusion
In this chapter we have reviewed the contribution of transcription to the levels of free histones and their influence on the cell cycle and DNA replication. Nucleosomes need to be disassembled to allow DNA transcription by RNA polymerases. An essential factor for disassembly/reassembly process during DNA transcription is the FACT complex. We concluded, using loss-of-function FACT mutants, that FACT dysfunction provokes downregulation of
Finally, we propose an attractive overall concept,
Acknowledgments
We thank Akash Gunjan´s and Vincent Geli´s labs for their fruitful collaboration. This work has been supported by the Spanish Ministry of Education and Science (grant BFU2007-67575-C03-02/BMC), by the Andalusian Government (grant P07-CVI02623) and by the European Union (FEDER). D.M. was covered by a F.P.I. fellowship from the Regional Andalusian Government and M. M-H. by a fellowship from the Spanish Ministry of Education and Science. We thank Helen Warburton for English corrections.
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