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Arsenic-induced Mre11 phosphorylation is cell cycle-dependent and defective in NBS cells
Shyng-Shiou F Yuan1, Jinu-Huang Su, Ming-Feng Hou
1Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan ROC. yuanssf@ms33.hinet.net
Abstract:
Cancer-prone diseases ataxia-telangiectasia (AT), Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia-like disorder (ATLD) are defective in the repair of DNA double-stranded break (DSB). On the other hand, arsenic (As) has been reported to cause DSB and to be involved in the occurrence of skin, lung and bladder cancers. To dissect the repair mechanism of As-induced DSB, wild type, AT and NBS cells were treated with sodium arsenite to study the complex formation and post-translational modification of Rad50/NBS1/Mre11 repair proteins. Our results showed that Mre11 went through cell cycle-dependent phosphorylation upon sodium arsenite treatment and this post-translational modification required NBS1 but not ATM. Defective As-induced Mre11 phosphorylation was rescued by reconstitution with full length NBS1 in NBS cells. Although As-induced Mre11 phosphorylation was not required for Rad50/NBS1/Mre11 complex formation, it might be required for the formation of Rad50/NBS1/Mre11 nuclear foci upon DNA damage.
Insights
Arsenic exposure causes DNA double-strand breaks (DSBs). Mre11 phosphorylation, crucial for DNA repair foci formation, requires NBS1 but not ATM in response to arsenic.
Area of Science:
- DNA repair mechanisms
- Environmental toxicology
- Cancer biology
Background:
- Ataxia-telangiectasia (AT), Nijmegen breakage syndrome (NBS), and ATLD are cancer-prone disorders linked to defective DNA double-strand break (DSB) repair.
- Arsenic (As) exposure is associated with DSBs and increased risk of skin, lung, and bladder cancers.
Purpose of the Study:
- To investigate the DNA repair mechanisms of arsenic-induced DSBs.
- To analyze the role of NBS1 and ATM in the post-translational modification and complex formation of Rad50/NBS1/Mre11 proteins following arsenic exposure.
Main Methods:
- Wild-type, AT, and NBS cells were treated with sodium arsenite.
- Analysis of Rad50/NBS1/Mre11 complex formation and Mre11 phosphorylation.
- Cell cycle analysis and rescue experiments with full-length NBS1.
Main Results:
- Sodium arsenite treatment induced cell cycle-dependent Mre11 phosphorylation.
- NBS1 was required for Mre11 phosphorylation, while ATM was not essential.
- Mre11 phosphorylation was not necessary for Rad50/NBS1/Mre11 complex assembly but may be vital for nuclear foci formation.
Conclusions:
- NBS1-dependent Mre11 phosphorylation is a key event in the cellular response to arsenic-induced DNA damage.
- This pathway is distinct from ATM-dependent signaling, suggesting a specific role in DSB repair foci formation.
- Understanding these mechanisms could inform strategies for mitigating arsenic-induced carcinogenesis.