DNA damage up-regulated protein (DDUP)

DNA damage up-regulated protein (DDUP) is a 186-amino acid microprotein encoded by the long non-coding RNA CTBP1 divergent transcript (CTBP1-DT), which is located on human chromosome 4p16.3[1][3]. Although transcribed as a lncRNA, CTBP1-DT harbors an open reading frame encoding DDUP, whose translation is rapidly upregulated in response to DNA damage through a post-transcriptional, cap-independent mechanism regulated by an internal ribosome entry site (IRES) and repressed by upstream open reading frames[1]. Upon DNA damage (e.g., caused by chemotherapeutic agents like cisplatin, etoposide, or ionizing radiation), DDUP is phosphorylated by ATR kinase, altering its structure and enabling it to retain the RAD18/RAD51C and RAD18/PCNA complexes at damaged chromatin sites, which is critical for both homologous recombination and post-replication repair[1][2][4][6]. Elevated DDUP supports cancer cell survival following chemotherapy by maintaining DNA repair signaling, conferring resistance to agents such as cisplatin; inhibition of ATR disrupts this process and restores chemosensitivity[1][5]. In addition to its protein-coding function, CTBP1-DT also acts as a regulatory lncRNA in cancer and other diseases, but only the protein (DDUP) is directly implicated in DNA repair and chemoresistance[3][5]. DDUP is being explored as a potential biomarker and therapeutic target in cancer, especially for overcoming chemoresistant disease[3][5].

Other names

CTBP1-DTCTBP1 divergent transcriptMGC21675C4orf42CTBP1-AS1CTBP1-AS2DDUPDNA damage up-regulated proteinCTBP1 antisense RNA 1 (head to head)CTBP1 antisense RNA 1 (non-protein coding)CTBP1 antisense RNA 2 (head to head)DNA damage-upregulated protein

Inhibition of ATR blocks DDUP-induced chromatin retention of DNA repair factors and sensitizes cancer cells to DNA-damaging agents