The effect of the nucleolar protein ZNF385A on the ribosomal DNA copy number variation in response to Cr(VI)-induced DNA damage

Hexavalent chromium [Cr(VI)] is a widely distributed carcinogen in industrial contexts and general environmental contexts. Emerging research highlights the central role of ribosomal DNA (rDNA) in DNA Damage Responses (DDRs). However, there remains a lack of investigation into the potential dose-dependent relationship between exposure to Cr(VI) and alterations in rDNA copy number (CN), as well as the related mechanisms underlying these effects. A molecular epidemiological investigation involving 67 workers exposed to Cr(VI) and 75 unexposed controls was conducted. There was a notable increase in ZNF385A expression, variations in rDNA CN, and elevated γH2AX levels in the peripheral blood of Cr(VI)-exposed workers. Restricted cubic spline (RCS) models showed that blood Cr levels in the exposed population exhibited non-linear dose-dependent relationships with γH2AX, rDNA CN, and ZNF385A. Of considerable interest, there were robust and positive associations between ZNF385A and both γH2AX and rDNA CN. Further in vitro experiments provided concrete evidence that Cr(VI) simultaneously caused an increase in ZNF385A expression and variations in rDNA CN. ZNF385A-depleted cells showed increased sensitivity to Cr(VI)-mediated DDRs and alterations in rDNA CN. This study indicated that ZNF385A played a highly significant role in the rDNA CN variation in response to Cr(VI)-induced DNA damage. [Display omitted] •Increased ZNF385A and rDNA copy number were observed in both humans and cells.•Cr was positively and non-linearly associated with rDNA copy number and ZNF385A.•ZNF385A expression was positively associated with γH2AX and rDNA copy number.•Nucleolar protein ZNF385A depletion generated instability of rDNA in vitro.•Cells deficient for ZNF385A were sensitive to Cr(VI)-induced DNA damage response.