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We hypothesized that the poor outcome associated with squamous cell carcinomas of the head and neck (SCCHN) may be attributed to by deficits in the DNA damage response. The histone protein variant, H2AX, is phosphorylated by the nuclear kinases ATM, ATR, and DNA-PK in response to several forms of DNA damage. This phosphorylation results in the formation of quantifiable nuclear foci of modified H2AX protein, called gamma-H2AX. Focus formation is thought to be an integral step in the repair of DNA breaks, as gamma-H2AX foci aid in retaining DNA repair factors, such as the MRN DNA repair complex, at the site of damage, facilitating repair. We observed a decrease in copy number of the H2AX gene in SCCHN cell lines using fluorescence in situ hybridization (FISH). We hypothesize that this insufficiency leads to a decreased amount of the gene product, resulting in attenuated focus formation following induction of DNA damage. This would translate into an abrogated DNA damage response, providing an increased number of unrepaired chromatin breaks or other cytogenetic aberrations in response to treatment with DNA damaging agents. To date, focus formation assays and breakage studies on SCCHN cell lines have shown that loss of H2AX correlates with decreased focus formation, increased chromosomal aberrations, and an attenuated damage response. Therefore, H2AX deficit and the resultant attenuated damage response may contribute to the poor prognosis in SCCHN patients.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]