Histone Phosphorylation And Human Diseases

In mammalian cells, DNA double-strand breaks (DSBs) are highly toxic lesions that, if not repaired or repaired incorrectly, can cause cell death, mutations, and chromosomal translocations and can lead to cancer. Phosphorylation of H2AX (^-H2AX) is induced in response to DSBs. A defective DNA damage response has caused some diseases, such as ataxia telangiectasia (AT) (Boder and Sedgwick, 1958), Seckel syndrome (O'Driscoll et al., 2003), Nijmegen breakage syndrome (Tauchi et al., 2002), Bloom's syndrome (Chester et al., 1998), ataxia telangiectasia-like disease (ATLD), Radiosensitive sever combined immunodeficiency (RS-SCID), LIG4 syndrome (O'Driscoll et al., 2004), Xeroderma pigmentosum (XP), Trichoth-iodystrophy (TTD) and Cockayne syndrome (CS)(Theron et al., 2005). In humans, mutations of the ATM gene cause AT, mutations of the ATR gene cause Seckel syndrome, mutations of the NBS1 gene cause Nijmegen breakage syndrome, mutations of the BLM gene cause Bloom's syndrome, mutations of the MRE11 gene cause ATLD, mutations of the Artemis gene, specifying a protein that plays a subsidiary role in non-homologous end-joining (NHEJ) although it is not an essential component, cause RS-SCID, mutations of DNA ligase IV, an essential component of DNA NHEJ, cause LIG4 syndrome, and mutations of XPD gene cause XP, TTD and CS (Table 2). For example, Seckel syndrome patients have dramatic microcephaly and marked growth and development delay, Nijmegen breakage syndrome is a recessive genetic disorder characterized by immunodeficiency with a high frequency of malignancies, and LIG4 syndrome is associated with pancytopenia, developmental and growth delay and dysmorphic facial features.

Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation, with some diagnostic features, such as skeletal abnormalities (Hanauer and Young, 2002; Young, 1988). Trivier et al., (1996) had data suggesting that CLS is caused by loss of function mutations in RSK2 (Trivier et al., 1996). RSK2 protein is a member of a family of serine/threonine protein kinases that act at the distal end of the mitogen induced Ras mitogen-activated protein kinase (MAPK) signaling pathway. It can phosphorylate histone H3 (S10) (see section 6).

Table 2. Syndromes and associated mutated genes

Syndrome

Mutated gene

Ataxia telangiectasia (AT) Seckel syndrome Nijmegen breakage syndrome Blooms syndrome

Ataxia telangiectasia like disease (ATLD)

ATM ATR Nbs1 BLM Mre11

Radiosensitive sever combined immunodeficiency (RS-SCID) Artemis

LIG4 syndrome Xeroderma pigmentosum (XP) Trichothiodystrophy (TTD) Cockayne syndrome

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