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 Atm^KD/KD mice, AtmR3016H (Atm^R/R ) mice were viable, immunodeficient, and displayed spontaneous craniofacial abnormalities and d

SUBMITTER: Milanovic M 

PROVIDER: S-EPMC8137556 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature