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.

CtIP 是一种 DNA 末端切除因子，广泛参与基于细胞的报告系统中的替代末端连接 (A-EJ) 介导的易位。为了解决 CtIP（一种必需基因）在易位介导的淋巴瘤发生中的生理作用，我们将小鼠 CtIP 的 T855A 突变引入非同源末端连接和 Tp53 双缺陷小鼠，这些小鼠通常死于携带 A-EJ 介导的 IgH- 的淋巴瘤。 Myc易位。CtIP 的 T855 在 DNA 损伤后被 ATM 或 ATR 激酶磷酸化以促进末端切除。在这里，我们报道了 CtIP 的 T855A 突变损害了Xrcc4 ^-/- Tp53 ^-/-小鼠的新生儿发育和DNA-PKcs ^-/- Tp53 ^-/-中 IgH-Myc 易位驱动的淋巴瘤发生老鼠。从机制上讲，T855A 突变限制了 DNA 末端切除长度，而不影响发夹开口、易位频率或叉稳定性。同时，在辐射后，CtIP-T855A 突变细胞显示出一致的 Chk1 磷酸化降低和 G2/M 细胞周期检查点的缺陷。与 T855A 突变在易位以外的淋巴瘤发生中的作用一致，CtIP-T855A 突变也延迟了 λ-Myc 小鼠的脾肿大。总的来说，我们的研究揭示了 CtIP-T855 磷酸化在 A-EJ 介导的染色体易位之外的淋巴瘤发生中的作用。