Role of BRCT motif containing proteins in Chk1 activation
© BioMed Central Ltd 2006
Published: 01 November 2006
Chk1, along with Chk2, regulates processes such as DNA replication, cell cycle control, chromatin restructuring and apoptosis. DNA damage/replication stress activates Chk1 by phosphorylation from the PI3/PI4 family of kinases. Activation of Chk1 is thought to be mediated by proteins containing the BRCA1 C-terminal domain (BRCT). We previously identified a potential complex of four Chk1-associated proteins by immunoprecipitation, western blotting and mass spectrometry, one of which is BRCA1. Germline mutations in BRCA1 are responsible for many cases of hereditary breast cancer, and cells deficient in BRCA1 sustain spontaneous aberrations in chromosome structure. Such findings indicate that BRCA1 is essential for suppressing genome instability.
Method and results
Inhibition of Chk1 activation in response to ionising radiation requires the loss of both TopBP1 and BRCA1, suggesting redundancy. In addition, as the response to hydroxyurea, or UV, was unaffected, it seems likely that different proteins are involved in Chk1 activation in response to differing stimuli. Analysis of other Chk1 binding proteins continues determining whether they are involved in Chk1 activation in response to stalled replication forks and/or double-stranded DNA breaks. As Chk1 is involved in maintaining tumor cell viability following activation of the replication checkpoint, the Chk1-regulated checkpoint(s) may protect cells from ionizing radiation-induced killing. The ability to delineate the control mechanisms of Chk1 is of critical importance in order to target Chk1 with the aim of increasing the selectivity and specificity of anticancer drug treatments.
Breast Cancer Campaign funded the project.