WRN Is Required for ATM Activation and the S-Phase Checkpoint in Response to Interstrand Cross-Link–Induced DNA Double-Strand Breaks

• DOI: 10.1091/mbc.e07-07-0698
• Publication Date: 2008-07-03T01:22:28Z
• Authors: Wen-Hsing Cheng; Diana Muftic; Meltem Muftuoglu; Lale Dawut; Christa Morris; Thomas Helleday; Yosef Shiloh; Vilhelm A. Bohr
• Keywords: CHEK1; Werner syndrome; DNA-PKcs; Chromosome instability; Checkpoint Kinase 2; Nijmegen breakage syndrome

Werner syndrome (WS) is a human genetic disorder characterized by extensive clinical features of premature aging. Ataxia-telengiectasia (A-T) multisystem genomic instability that includes aging in some the patients. WRN and ATM, proteins defective WS A-T, respectively, play significant roles maintenance stability are involved several DNA metabolic pathways. A role for repair has been proposed; however, this study provides evidence also ATM pathway activation S-phase checkpoint cells exposed to interstrand cross-link-induced double-strand breaks. Depletion such RNA interference results an intra-S defect, interferes with as well downstream phosphorylation target proteins. Treatment under replication stress kinase inhibitor KU 55933 defect similar observed shRNA cells. Moreover, gamma H2AX levels higher than control 6 16 h after exposure psoralen cross-links. These suggest participate response, which facilitates collapsed forks.