The human decatenation checkpoint

Hsp90-inhibitor geldanamycin abrogates G2 arrest in p53-negative leukemia cell lines through the depletion of Chk1

“…Therefore, G 2 abrogation by GM may not be solely attributed to Chk1 depletion. Involvement of Chk1 in the decatenation checkpoint mechanism had been ruled out because of the lack of its activation after 2 h of incubation with ICRF-193 in a previous report (Deming et al, 2001). However, treatment with 1.2 mM of ICRF-193 for 24 h clearly induced Chk1 phosphorylation at Ser345 in Jurkat cells, whose extent was much stronger than that induced by 50 nM doxorubicin.…”

The decatenation checkpoint

“…The original report documented a functional checkpoint in the Indian muntjac cells, PtK2 rat kangaroo cells, Chinese hamster ovary cells, SV-MRC5-transformed human fibroblasts, MSU1.1 v-myc-immortalised human fibroblasts, and HeLa human cervical carcinoma cell lines (Downes et al, 1994). Subsequently, the checkpoint was observed in human lymphoblastoid cell lines (Deming et al, 2001), mouse embryonic fibroblasts (Damelin et al, 2005), and primary cultures and strains of human uroepithelial cells (Doherty et al, 2003) and human fibroblasts (Kaufmann and Kies, 1998;Deming et al, 2001;Franchitto et al, 2003;Damelin et al, 2005).…”

“…Decatenation checkpoint signalling depends on ATR (ATM-and Rad3-related) kinase, as overexpression of a dominant-negative ATR prevented an efficient response (Deming et al, 2001). The checkpoint response does not require ATM kinase (Deming et al, 2001).…”

“…Expression of a constitutively nuclear cyclin B1 overrode the decatenation checkpoint (Deming et al, 2002). Checkpoint function also requires BRCA1: a checkpoint defect was observed in HCC1937 cells (which have a homozygous BRCA1 mutation) and the defect was reversed when wild-type BRCA1 was expressed in those cells (Deming et al, 2001). Checkpoint activity was found to be impaired in cells from four Werner Syndrome patients and was restored when WRN (Werner helicase) was expressed, which indicated a role for WRN in the decatenation checkpoint (Franchitto et al, 2003).…”

“…The decatenation checkpoint does not require ATM kinase function, as the checkpoint was intact in cells from three ataxia telangiectasia (A-T) patients with mutations in ATM (Deming et al, 2001). In contrast, the DNA damage checkpoint requires ATM and was impaired in A-T cells.…”