Impact of Nuclear De Novo NAD⁺ Synthesis via Histone Dynamics on DNA Repair during Cellular Senescence To Prevent Tumorigenesis

ABSTRACT

NAD⁺ synthesis is a fundamental process in living cells. The effects of local metabolite production on chromatin influence the epigenetic status of chromatin in DNA metabolism. We have previously shown that K5 acetylation of H2AX by TIP60 is required for the ADP ribosylation activity of PARP-1, for histone H2AX exchange at DNA damage sites. However, the detailed molecular mechanism has remained unclear. Here, we identified de novo NAD synthetase 1 (NAD syn1) as a novel binding partner to H2AX. The enzymatic activity of NAD syn1 is crucial for the ADP ribosylation activity of PARP-1 for the H2AX dynamics at sites of DNA damage. Inhibition of the NAD synthetase activity in the cell nucleus decreased the overall cellular NAD⁺ concentration, leading to cellular senescence. Accordingly, the acetylation-dependent H2AX dynamics and homologous recombination repair were suppressed, leading to increased tumorigenesis. Our findings have revealed the importance of de novo NAD⁺ production in the cell nucleus for protection against the decreased DNA repair capacity caused by cellular senescence and thus against tumorigenesis.

KEYWORDS:

• DNA damage
• NAD synthetase 1
• TIP60
• acetylation
• cellular senescence
• histone H2AX
• tumorigenesis

Declaration of Interests

The authors declare no conflict of interest.

SUPPLEMENTAL MATERIAL

Supplemental material is available online only.

ACKNOWLEDGMENTS

We thank Takuma Shiraki for critical comments and helpful suggestions. This work was supported by Grant-in-Aid for Scientific Research (B: 20H04336), a grant from Suzuken Memorial Foundation to T.I. Grant-in-Aid for Scientific Research (C: 19K12321), to M.I. This work was also partly supported by the Cooperative Research Project Program at the IDAC, Tohoku University, and “Strategic Research Projects” grant from ROIS to K.F.