Gromoll J, Lahrmann L, Godmann M, Müller T, Michel C, Stamm S, Simoni M. Genomic checkpoints for exon 10 usage in the luteinizing hormone receptor type 1 and type 2. Mol Endocrinol.
In the absence of genome checkpoint functions, telomere dysfunction accelerates genomic instability, facilitating tumor initiation [ 5].
Amp, amplification; CGH, comparative genomic hybridization; Chk1, checkpoint kinase 1; FADD, Fas-associated death domain; Pak1, p21-activated kinase 1.
CISH: chromogenic in situ hybridization; ER: estrogen receptor; CGH: comparative genomic hybridization; Chk1: checkpoint kinase 1; FADD: Fas-associated death domain; FISH: fluorescence in situ hybridization; HNSCC: head and neck squamous cell carcinoma; ICC: immunocytochemistry; IHC: immunohistochemical; LOH: loss of heterozygosity; PR: progesterone receptor; RFS: recurrence-free survival.
The disease Ataxia telangiectasia (ATM-deficiency) has been associated with defects in the activation of p53, G1/S, intra-S, and G2/S cell cycle checkpoints, genomic instability, enhanced radiosensitivity and increased incidence of lymphoid tumours [ 33, 61].
Such coordination has been proposed for other tumor suppressors involved in the maintenance of genomic integrity including the checkpoint kinase Chk1 and the DNA damage binding protein DDB2 [60], [61], [61].
The G1/S checkpoint protects genomic integrity and prevents damaged cells from entering S-phase by inducing apoptosis [ 46- 48].
In addition to the increased rate in generating genomic alterations, inactivation of checkpoint and genomic surveillance genes is critical during the development of GIN by allowing the accumulation of gene mutations, chromosome damage and ploidy abnormalities.
To maintain genomic stability, cells have checkpoint and DSB repair systems to respond to DNA damage throughout most of the cell cycle.
Cells with a stressed mitotic checkpoint accumulate genomic aberrations [ 40, 41], but are subject to the p53-dependent G1 post-mitotic checkpoint, which acts as an additional barrier against proliferation of aberrant cells [ 46].
