| First Author | Milanovic M | Year | 2021 |
| Journal | Cancer Res | Volume | 81 |
| Issue | 2 | Pages | 426-437 |
| PubMed ID | 33239428 | Mgi Jnum | J:320768 |
| Mgi Id | MGI:6879212 | Doi | 10.1158/0008-5472.CAN-20-2447 |
| Citation | Milanovic M, et al. (2021) The Cancer-Associated ATM R3008H Mutation Reveals the Link between ATM Activation and Its Exchange. Cancer Res 81(2):426-437 |
| abstractText | 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 Atm(KD/KD) mice, AtmR3016H (Atm(R/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. |
