Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability

In our previous study, we reported that sirtuin5 (SIRT5), a member of the NAD + -dependent class III histone deacetylase family, is highly expressed in colorectal cancer (CRC). Herein we show that SIRT5 knockdown impairs the production of ribose-5-phosphate, which is essential for nucleotide synthesis, resulting in continuous and irreparable DNA damage and consequently leading to cell cycle arrest and enhanced apoptosis in CRC cells. These SIRT5 silencing-induced effects can be reversed by nucleoside supplementation. Mechanistically, SIRT5 activates transketolase (TKT), a key enzyme in the non-oxidative pentose phosphate pathway, in a demalonylation-dependent manner. Furthermore, TKT is essential for SIRT5-induced malignant phenotypes of CRC both in vivo and in vitro. Altogether, SIRT5 silencing induces DNA damage in CRC via post-translational modifications and inhibits tumor growth, suggesting that SIRT5 can serve as a promising target for CRC treatment. Sirtuin 5 (SIRT5) has been associated to colorectal cancer and metabolic regulation. Here, the authors show that SIRT5 silencing reduces nucleotide availability leading to DNA damage and tumor suppression in colorectal cancer models.