DNA damage–induced phosphorylation of CtIP at a conserved ATM/ATR site T855 promotes lymphomagenesis in mice
Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la phosphorylation de la thréonine 855 de la protéine CtIP, induite par les dommages causés à l'ADN, favorise la lymphomagenèse
Upon DNA damage, ATM and ATR kinase phosphorylate CtIP at T855 and several other sites. This study identified a physiological role of DNA damage–induced CtIP phosphorylation at T855 using mouse models. Specifically, we showed that while not affecting normal development and physiological DNA repair in developing lymphocytes, the T885A mutation of CtIP reduced the extent of DNA end resection, compromised the maintenance of the DNA damage–induced G2/M checkpoints, and delayed Myc-induced lymphomagenesis.CtIP is a DNA end resection factor widely implicated in alternative end-joining (A-EJ)–mediated translocations in cell-based reporter systems. To address the physiological role of CtIP, an essential gene, in translocation-mediated lymphomagenesis, we introduced the T855A mutation at murine CtIP to nonhomologous end-joining and Tp53 double-deficient mice that routinely succumbed to lymphomas carrying A-EJ–mediated IgH-Myc translocations. T855 of CtIP is phosphorylated by ATM or ATR kinases upon DNA damage to promote end resection. Here, we reported that the T855A mutation of CtIP compromised the neonatal development of Xrcc4−/−Tp53−/− mice and the IgH-Myc translocation-driven lymphomagenesis in DNA-PKcs−/−Tp53−/− mice. Mechanistically, the T855A mutation limits DNA end resection length without affecting hairpin opening, translocation frequency, or fork stability. Meanwhile, after radiation, CtIP-T855A mutant cells showed a consistent decreased Chk1 phosphorylation and defects in the G2/M cell cycle checkpoint. Consistent with the role of T855A mutation in lymphomagenesis beyond translocation, the CtIP-T855A mutation also delays splenomegaly in λ-Myc mice. Collectively, our study revealed a role of CtIP-T855 phosphorylation in lymphomagenesis beyond A-EJ–mediated chromosomal translocation.All study data are included in the article and/or SI Appendix.