H3 replacement variants

While the synthesis of histones increases dramatically during DNA replication (see Ref. [99]), some variants are synthesized and incorporated into chromatin in absence of replication [100] these have been referred to as replication independent, basal, or replacement variants. Some variants show a mixed pattern with increased synthesis during replication, but continued expression in non-dividing cells (see Ref. [3], pp. 103-109). Several of the variants discussed above can be considered specialized replacement variants, including CENP-A [22], H2A.Z [35,100], H2A.X [56,100], and probably macroH2A. This section focuses on H3.3, an H3 replacement variant found in animals. 

3 is distinguished from H3 replication coupled variants by four sequence differences at amino acids 31, 87, 89, and 90 [101,102]. These differences are conserved between mammals and Drosophila, indicating that they are functionally significant [103]. 

A recent study in Drosophila cells used H3-GFP fusion proteins to compare the deposition patterns of H3.3 and a replication dependent H3 [104]. The deposition of the replication dependent H3-GFP occurred at sites that co-localized with BrdU 

One possible function for H3.3 and some of the other replacement variants is to maintain the integrity of chromatin structure by replacing histones that are damaged or lost during normal cellular metabolism. Ahmad and Henikoff [104] suggested that replication independent incorporation of H3.3 could provide a mechanism to switch patterns of histone modification by removing H3 molecules that may be irreversibly modified by methylation. They also suggested that H3.3 could serve as a mark of transcriptionally active chromatin. One complication for 

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H3 replacement variants are also present in plants [108] and Tetrahymena [109]. Phylogenetic analyses indicates that these H3 replacement variants arose independently of animal H3.3 [109]. Like H3.3, the plant H3 replacement variant also appears to be preferentially deposited into transcriptionally active chromatin [110]. The H3 replacement variant in Tetrahymena, hv2, is found only in the transcriptionally active macronucleus [49]. In contrast to H3.3, the amino acid differences between hv2 and the replication dependent H3 of Tetrahymena do not appear to be essential for replication independent incorporation into chromatin [111]. In this case constitutive expression appears to be the dominant factor that can drive replication independent deposition of hv2 or an H3 variant that is normally replication dependent. This difference between hv2 and H3.3 is not necessarily surprising because hv2 appears to have arisen independently of H3.3 and does not have the structural features characteristic of H3.3 [109]. 

Yu, L. and Gorovsky, M.A. (1997) Constitutive expression, not a particular primary sequence, is the important feature of the H3 replacement variant hv2 in Tetrahymena thermophila. Mol. Cell. 

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