The contribution of mitochondrial thymidylate synthesis in preventing the nuclear genome stress

Ming Hsiang Lee, Liya Wang, Zee Fen Chang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

16 Scopus citations

Abstract

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, we provide evidence that mitochondrial thymidylate synthesis via thymidine kinase 2 (TK2) is a limiting factor for the repair of ultraviolet (UV) damage in the nuclear compartment in quiescent fibroblasts. We found that TK2 deficiency causes secondary DNA double-strand breaks formation in the nuclear genome of quiescent cells at the late stage of recovery from UV damage. Despite slower repair of quiescent fibroblast deficient in 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. Here, we conclude that 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.

Original languageEnglish
Pages (from-to)4972-4984
Number of pages13
JournalNucleic Acids Research
Volume42
Issue number8
DOIs
StatePublished - 04 2014
Externally publishedYes

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