ReviewH2AX: the histone guardian of the genome
Section snippets
Introduction: the tale of a tail
Just as the nucleic acid base is the fundamental repeating unit of DNA, the nucleosome forms the basic building block of chromatin. Within each nucleosome, 147 base-pairs of DNA are wrapped 1.7 times around a central core of eight histone protein molecules (an octamer consisting of two copies each of H2A, H2B, H3, and H4 histones) that form a 100 kDa protein complex [1]. Each core histone contains a “globular domain,” which is necessary for histone–histone and histone–DNA contacts, as well as a
γ-H2AX marks the spot
The presence of two evolutionary conserved pathways, homologous end joining (NHEJ) and homologous recombination (HR), for the repair of DNA double strand breaks (DSBs) highlights the threat to genomic integrity caused by free DNA ends [8]. A role for H2AX in the DNA damage response was first suggested by William Bonner and co-workers who used two-dimensional gel analysis to show that phosphorylated H2AX formed rapidly following exposure of cells to ionizing radiation [5]. The phosphorylation
Who rings the H2AX serine 139 bell?
Following the generation of DSBs a rapid kinase-based signaling pathway is activated that coordinates DNA repair with the induction cell-cycle checkpoints [22], [23]. The principal mediators in this pathway are the phosphatidylinositol-3 kinase-like family of kinases (PIKK). At least four PIKK family members are involved in the transduction of the signal that originates at broken DNA: ataxia telangiectasia mutated (ATM) ATM-and Rad3-related (ATR) ATM related kinase (ATX), and DNA dependent
Race to the break
The recruitment of DNA damage signaling and repair proteins to sites of genomic damage constitutes a primary event triggered by DNA damage. Many components of the DNA damage response, including ATM, BRCA1, 53BP1, MDC1, RAD51, and the MRE11/RAD50/NBS1 (MRN) complex [12], [21], [32], [33], [34], [35], [36] form ionizing radiation induced foci (IRIF) that co-localize with γ-H2AX foci. These nuclear micro-domains are thought to contain hundreds to thousands of molecules that accumulate in the
The H2AX syndrome
Hereditary diseases affecting the cellular response to DSBs include ataxia telangiectasia (defective ATM), Nijmegen breakage syndrome (defective Nbs1) and Bloom’s syndrome (defective BLM). The hallmarks of these disorders are growth defects, immunodeficiency, hypogonadism, hypersensitivity to specific DNA damaging agents, chromosomal fragility, and cancer predisposition. Mouse models in which specific components of the DSB repair/signaling pathway are disrupted recapitulate most of the
Role of H2AX in DNA repair
The first experiment that demonstrated a role for H2AX in DNA repair was a genetic study performed in Saccharomyces cerevisiae [51]. Elimination of the unique C-terminal H2A serine residue in yeast led to an impairment in NHEJ [51]. More recently, it was shown that in S. cerevisiae H2A Ser 129 is critical for the efficient repair of DSBs during DNA replication [52]. The analysis of H2AX-deficient ES cells and mice showed that H2AX is not essential for NHEJ or HR in mammalian cells, but does
Role of H2AX in genomic stability and cell cycle checkpoints
Genomic instability is a general term used to describe a genetic propensity for an increase in chromosomal pathology secondary to inaccurate repair or deficiency in cell cycle checkpoints. Typically, the instability can be visualized as chromosomal breaks, translocations, or aneuploidy. H2AX-deficient mouse embryo fibroblasts and T cells contain chromosomal breaks and translocations. However, H2AX−/− B-cells do not show such aberrations, presumably because the apoptotic machinery eliminates B
Role of H2AX in growth
Like other mouse models of genomic instability, H2AX deficient mice are small in size [39]. This growth defect is distributed proportionally throughout the entire organism. Similarly, H2AX−/− mouse embryonic fibroblasts (MEFs) exhibit impaired growth and senesce after only 3–4 passages in culture [39], a phenotype partially alleviated by p53 deficiency [49]. In human cells, senescence is associated with telomere erosion that follows every cell division [55]. Moreover, a number of proteins
Role of H2AX in meiosis
Meiosis is a cellular differentiation program during which physiological DSBs are created and repaired, giving rise to recombination events between parental chromosomes. Meiotic recombination takes place in the prophase stage within the first of two meiotic divisions, and is triggered by DSBs generated by the Spo11 transesterase [58]. When the distribution of γ-H2AX is analyzed in mouse spermatocytes, it shows two distinct patterns of staining [19]. On the one hand, there is a Spo11-dependent
Role of H2AX tumor suppression
There is mounting evidence that genomic instability is a cause and not just a consequence of cancer development [8]. Although chromosomes in cells from H2AX deficient mice contain frequent breaks and translocations, there is little or no increase in tumor development in H2AX−/− mice [49], [50]. Apparently, H2AX−/− cells are protected from malignant transformation by the activity of DNA damage sensors, like p53. Such ‘gatekeepers’ [64] proteins provide a safeguard against genomic instability by
Role of H2AX in immune receptor rearrangements
During lymphocyte development, T and B cells undergo the process of somatic gene rearrangement known as Variable Diversity Joining (V(D)J) recombination to produce the primary antigen receptor repertoire. Antigen receptor diversification in lymphocytes is initiated by the RAG-1/2 endonuclease, which introduces DSBs adjacent to the antigen receptor segments (V, D, and J segments) [65]. The subsequent juxtaposition and ligation of V(D)J ends requires ubiquitously expressed proteins (Ku80, Ku70,
Model for H2AX function
We speculate that the pleotropic phenotypes observed in the absence of H2AX- chromosomal instability and radiation sensitivity in mitotic cells, abnormalities in XY pairing and transcriptional inactivation in spermatocytes, defects in G2/M checkpoint control, and reduced levels of class-switching are all due to two complementary structural functions provided by the phosphorylation marks on H2AX: a role in (1) the focal assembly and retention of factors in chromatin regions near the damaged site
Implications for human disease
The histone H2AX gene, located 11 Mb telomeric to ATM at 11q23.3, is in a region commonly deleted or translocated in several human hematological malignancies and solid tumors [75]. Heterozygous deletion of chromosome bands 11q22-q23 is detected at a particularly high frequency in B cell chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma (MCL), and T cell prolymphocytic leukemia (T-PLL), and is associated with rapid disease progression and poor survival in B-CLL [75], [76]. Since somatic
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