The ATM–Chk2 and ATR–Chk1 pathways in DNA damage signaling and cancer

Smith, J., Mun Tho, L., Xu, N. and Gillespie, D.A. (2010) The ATM–Chk2 and ATR–Chk1 pathways in DNA damage signaling and cancer. Advances in Cancer Research, 108(2010), pp. 73-112. (doi: 10.1016/B978-0-12-380888-2.00003-0) (PMID:21034966)

Abstract

DNA damage is a key factor both in the evolution and treatment of cancer. Genomic instability is a common feature of cancer cells, fuelling accumulation of oncogenic mutations, while radiation and diverse genotoxic agents remain important, if imperfect, therapeutic modalities. Cellular responses to DNA damage are coordinated primarily by two distinct kinase signaling cascades, the ATM–Chk2 and ATR–Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. Historically, these pathways were thought to act in parallel with overlapping functions; however, more recently it has become apparent that their relationship is more complex. In response to DSBs, ATM is required both for ATR–Chk1 activation and to initiate DNA repair via homologous recombination (HRR) by promoting formation of single-stranded DNA at sites of damage through nucleolytic resection. Interestingly, cells and organisms survive with mutations in ATM or other components required for HRR, such as BRCA1 and BRCA2, but at the cost of genomic instability and cancer predisposition. By contrast, the ATR–Chk1 pathway is the principal direct effector of the DNA damage and replication checkpoints and, as such, is essential for the survival of many, although not all, cell types. Remarkably, deficiency for HRR in BRCA1- and BRCA2-deficient tumors confers sensitivity to cisplatin and inhibitors of poly(ADP-ribose) polymerase (PARP), an enzyme required for repair of endogenous DNA damage. In addition, suppressing DNA damage and replication checkpoint responses by inhibiting Chk1 can enhance tumor cell killing by diverse genotoxic agents. Here, we review current understanding of the organization and functions of the ATM–Chk2 and ATR–Chk1 pathways and the prospects for targeting DNA damage signaling processes for therapeutic purposes.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Ms Joanne and Gillespie, Professor David
• Authors: Smith, J., Mun Tho, L., Xu, N., and Gillespie, D.A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Advances in Cancer Research
• Publisher: Academic Press
• ISSN: 0065-230X
• Published Online: 27 October 2010