The Cancer-Associated ATM R3008H Mutation Reveals the Link between ATM Activation and Its Exchange.

Abstract

ATM kinase is a tumor suppressor and a master regulator of the DNA damage response. Most cancer-associated alterations to ATM are missense mutations at the PI3-kinase regulatory domain (PRD) or the kinase domain. Expression of kinase-dead (KD) ATM protein solely accelerates lymphomagenesis beyond ATM loss. To understand how PRD suppresses lymphomagenesis, we introduced the cancer-associated PRD mutation R3008H (R3016 in mouse) into mice. R3008H abrogated DNA damage- and oxidative stress-induced activation of ATM without consistently affecting ATM protein stability and recruitment. In contrast to the early embryonic lethality of AtmKD/KD mice, AtmR3016H (AtmR/R ) mice were viable, immunodeficient, and displayed spontaneous craniofacial abnormalities and delayed lymphomagenesis compared with Atm-/- controls. Mechanistically, R3008H rescued the tardy exchange of ATM-KD at DNA damage foci, indicating that PRD coordinates ATM activation with its exchange at DNA-breaks. Taken together, our results reveal a unique tumorigenesis profile for PRD mutations that is distinct from null or KD mutations. SIGNIFICANT: This study functionally characterizes the most common ATM missense mutation R3008H in cancer and identifies a unique role of PI3-kinase regulatory domain in ATM activation.

• Authors: Maja Milanovic, Lisa M Houghton, Demis Menolfi, Ji-Hoon Lee, Kenta Yamamoto, Yang Li, Brian J Lee, Jun Xu, Verna M Estes, Dong Wang, Peter J Mckinnon, Tanya T Paull, Shan Zha
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 2 Pg. 426-437 (01 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 33239428 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Ataxia Telangiectasia Mutated Proteins

Topics

• Animals
• Ataxia Telangiectasia (genetics, metabolism)
• Ataxia Telangiectasia Mutated Proteins (genetics, metabolism)
• Cell Cycle Checkpoints (genetics)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cells, Cultured
• DNA Damage
• Disease Models, Animal
• Embryo, Mammalian (cytology)
• Fibroblasts (cytology, metabolism)
• Humans
• Kaplan-Meier Estimate
• Lymphocytes (metabolism, pathology)
• Mice, Knockout
• Mice, Transgenic
• Mutation
• Neoplasms (genetics, metabolism)