At present, a lot is known about biochemical aspects of double strand breaks (DBS) repair but how
chromatin structure affects this process and the sensitivity of
DNA to
DSB induction is still an unresolved question.
Ataxia telangiectasia (A-T) patients are characterised by very high sensitivity to
DSB-inducing agents such as ionising radiation. This radiosensitivity is revealed with an enhancement of
chromosomal instability as a consequence of defective DNA repair for a small fraction of breaks located in the
heterochromatin, where they are less accessible. Besides, recently it has been reported that
Ataxia Telangiectasia Mutated (ATM) mediated signalling modifies
chromatin structure. In order to study the impact of
chromatin compaction on the
chromosomal instability of A-T cells, the response to
trichostatin-A, an
histone deacetylase inhibitor, in normal and A-T lymphoblastoid cell lines was investigated testing its effect on
chromosomal aberrations, cell cycle progression, DNA damage and repair after exposure to X-rays. The results suggest that the response to both
trichostatin-A pre- and continuous treatments is independent of the presence of either functional or mutated
ATM protein, as the reduction of chromosomal damage was found also in the wild-type cell line. The presence of
trichostatin-A before exposure to X-rays could give rise to prompt DNA repair functioning on
chromatin structure already in an open conformation. Differently,
trichostatin-A post-treatment causing hyperacetylation of
histone tails and reducing the heterochromatic
DNA content might diminish the requirement for ATM and favour DSBs repair reducing chromosomal damage only in A-T cells. This fact could suggest that
trichostatin-A post-treatment is favouring the slow component of
DSB repair pathway, the one impaired in absence of a functionally
ATM protein. Data obtained suggest a fundamental role of
chromatin compaction on
chromosomal instability in A-T cells.