Histones, known as H1, H2A, H2B, H3, and H4, are small, evolutionarily conserved proteins. They have a high lysine and arginine content, which gives them a positive charge at physiological pH. This positive charge allows them to form ionic bonds with negatively charged DNA. Histones, along with ions like Mg2+, help neutralize the negatively charged phosphate groups of DNA.

The core of a nucleosome is made up of two molecules each of H2A, H2B, H3, and H4. These histones form an octameric structure called nucleosome "beads." A segment of double-stranded DNA is wrapped around this core, resulting in negative supercoiling due to the elimination of a helical turn. The N-terminal ends of these histones can undergo reversible covalent modifications such as acetylation, methylation, or phosphorylation. These modifications influence the tightness of histone binding to DNA and consequently affect the expression of specific genes. This process is an example of epigenetics, where heritable changes in gene expression occur without altering the nucleotide sequence. H1 histone binds to the linker DNA chain between nucleosomes, rather than being part of the nucleosome core. H1 is the most tissue-specific and species-specific histone, facilitating the compaction of nucleosomes into more compact structures.

Nucleosomes can be further packed together to form a nucleofilament, which takes the shape of a coil commonly referred to as a 30-nm fiber. This fiber is organized into loops anchored by a nuclear scaffold containing several proteins. Further levels of organization lead to the final structure of chromosomes.

During DNA replication, parental nucleosomes are disassembled to allow access to DNA. Once DNA is synthesized, nucleosomes rapidly form again. Histone proteins for nucleosome formation come from both de novo synthesis and the transfer of parental histones.

Despite the proofreading system employed during DNA synthesis, errors can still occur. These errors include incorrect base-pairing or the insertion of extra nucleotides. Additionally, DNA is constantly subjected to environmental factors that can alter or remove nucleotide bases. The damaging agents can be chemicals like nitrous acid or radiation such as nonionizing ultraviolet (UV) radiation and high-energy ionizing radiation. Spontaneously, bases in mammalian DNA are also altered or lost at a significant rate. If the damage is not repaired, it can introduce permanent changes (mutations) that can have deleterious effects, including loss of control over cell proliferation, leading to cancer. Fortunately, cells have efficient DNA repair mechanisms. Most repair systems involve recognizing the damage on DNA, excising or removing the damage, filling the gap with DNA synthesis using the sister strand as a template, and ligating the repaired DNA. These excision repair systems can remove one to tens of nucleotides. Repair synthesis of DNA can occur outside of the S phase.

Mismatch repair (MMR) is a process that corrects replication errors where mismatches of one to several bases occur. In E. coli, MMR is mediated by a group of proteins known as the Mut proteins. Homologous proteins are also present in humans. MMR occurs within minutes of replication and significantly reduces the error rate of replication from 1 in 107 to 1 in 109 nucleotides.
There are five classes of histones, designated H1, H2A, H2B, H3, and H4. These small, evolutionally conserved proteins are positively charged at physiologic pH as a result of their high content of lysine and arginine. Because of their positive charge, they form ionic bonds with negatively charged DNA. Histones, along with ions such as Mg2+ , help neutralize the negatively charged DNA phosphate groups.
1. Nucleosomes: Two molecules each of H2A, H2B, H3, and H4 form the octameric core of the individual nucleosome “beads.” Around this structural core, a segment of dsDNA is wound nearly twice (Fig. 30.26). Winding eliminates a helical turn, causing negative supercoiling. [Note: The N-terminal ends of these histones can be acetylated, methylated, or phosphorylated. These reversible covalent modifications influence how tightly the histones bind to the DNA, thereby affecting the expression of specific genes. Histone modification is an example of epigenetics, or heritable changes in gene expression caused without alteration of the nucleotide sequence.] Neighboring nucleosomes are joined by linker DNA ~50 bp long. H1 is not found in the nucleosome core, but instead binds to the linker DNA chain between the nucleosome beads. H1 is the most tissue specific and species specific of the histones. It facilitates the packing of nucleosomes into more compact structures.
2. Higher levels of organization: Nucleosomes can be packed more tightly (stacked) to form a nucleofilament. This structure assumes the shape of a coil, often referred to as a 30-nm fiber. The fiber is organized into loops that are anchored by a nuclear scaffold containing several proteins. Additional levels of organization lead to the final chromosomal structure (Fig. 30.27).
B. Nucleosome fate during DNA replication
Parental nucleosomes are disassembled to allow access to DNA during replication. Once DNA is synthesized, nucleosomes form rapidly. Their histone proteins come both from de novo synthesis and from the transfer of parental histones.
VI. DNA REPAIR
Despite the elaborate proofreading system employed during DNA synthesis, errors (including incorrect base-pairing or insertion of one to a few extra nucleotides) can occur. In addition, DNA is constantly being subjected to environmental insults that cause the alteration or removal of nucleotide bases. The damaging agents can be either chemicals (for example, nitrous acid, which can deaminate bases) or radiation (for example, nonionizing ultraviolet [UV] radiation, which can fuse two pyrimidines adjacent to each other in the DNA, and high-energy ionizing radiation, which can cause double-strand breaks). Bases are also altered or lost spontaneously from mammalian DNA at a rate of many thousands per cell per day. If the damage is not repaired, a permanent change (mutation) is introduced that can result in any of a number of deleterious effects, including loss of control over the proliferation of the mutated cell, leading to cancer. Luckily, cells are remarkably efficient at repairing damage done to their DNA. Most of the repair systems involve recognition of the damage (lesion) on the DNA, removal or excision of the damage, replacement or filling the gap left by excision using the sister strand as a template for DNA synthesis, and ligation. These excision repair systems remove one to tens of nucleotides. [Note: Repair synthesis of DNA can occur outside of the S phase.]
A. Mismatch repair
Sometimes replication errors escape the proofreading activity during DNA synthesis, causing a mismatch of one to several bases. In E. coli, mismatch repair (MMR) is mediated by a group of proteins known as the Mut proteins (Fig. 30.28). Homologous proteins are present in humans. [Note: MMR occurs within minutes of replication and reduces the error rate of replication from 1 in 107 to 1 in 109 nucleotides.] 1.