粒腺體內胸腺嘧啶激酶2對於維持核內基因體完整性之貢獻

Abstract

在休眠的纖維母細胞中，細胞質裡負責胸苷三磷酸(dTTP)合成的酵素表現量下降，導致胸苷三磷酸的量也顯著地下降。本篇論文研究闡釋了在這些休眠的纖維母細胞中，由粒腺體內胸腺嘧啶激酶2 (thymidine kinase 2) 所催化合成的胸苷酸(thymidylate)為紫外光照射後核內DNA修復之限制因子，並且在修復的後期，胸腺嘧啶激酶2缺失的細胞會有第二級的DNA雙股斷裂之發生。但是即便胸腺嘧啶激酶2缺失的細胞修復狀況較慢，最後DNA損傷的信號都會消失，並且這些修復後的休眠細胞在血清的刺激下也都可以再次地進入S細胞週期。而這些細胞在下一個G1細胞週期時會產生明顯的53BP1核小體 (53BP1 nuclear body)，意味著這些細胞有嚴重的基因體壓力。總結，在暫時休眠的纖維母細胞中，粒腺體內胸腺嘧啶激酶2所催化合成的胸苷酸可以幫助紫外光照射後核內DNA有效及正確地修復以保持基因體的完整性。

In quiescent fibroblasts, the expression levels of cytosolic enzymes for thymidine triphosphate (dTTP) synthesis are down-regulated, causing a marked reduction in the dTTP pool. In this study, the data indicate that mitochondrial thymidylate synthesis via thymidine kinase 2 (TK2) is a limiting factor for the repair of UV damage in the nuclear compartment in quiescent fibroblasts. Moreover, TK2 deficiency causes secondary DNA double-strand breaks (DSBs) formation in the nuclear genome of quiescent cells at the late stage of recovery from UV damage. Despite of slower repair in quiescent fibroblast deficient of TK2, DNA damage signals eventually disappeared, and these cells were capable of re-entering the S phase after serum stimulation. However, these cells displayed severe genome stress as revealed by the dramatic increase in 53BP1 nuclear body in the G1 phase of the successive cell cycle. In conclusion, mitochondrial thymidylate synthesis via TK2 plays a role in facilitating the quality repair of UV damage for the maintenance of genome integrity in the cells that are temporarily arrested in the quiescent state.