Open AccessDNA damage–induced phosphorylation of CtIP at a conserved ATM/ATR site T855 promotes lymphomagenesis in mice
Author(s) -
Xiaobin S. Wang,
Demis Menolfi,
Foon Wu-Baer,
Marco Fangazio,
Stefanie N. Meyer,
Zongping Shao,
Yunyue Wang,
Yimeng Zhu,
Brian J. Lee,
Verna M. Estes,
Olivia M Cupo,
Jean Gautier,
Laura Pasqualucci,
Riccardo DallaFavera,
Richard Baer,
Shan Zha
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2105440118
Subject(s) - dna damage , phosphorylation , biology , dna , mutation , dna repair , cancer research , dna pkcs , microbiology and biotechnology , genetics , gene
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.