Abstract 3654: The role of structure-specific endonuclease MUS81 in the induction of cytosolic DNA in tumor cells

Abstract

Abstract Genomic DNA is constantly damaged by endogenous and exogenous agents. The DNA damage response (DDR) is vital for recognizing DNA damage and instigating DNA repair reactions to ensure genome stability. MUS81 is a structure-specific endonuclease that is required for resolving stalled replication forks at sites of DNA damage to initiate Homologous Recombination repair. Our preliminary data suggests that the potentially detrimental DNA structures cleaved by MUS81 accumulate in the cytosol of many tumor cells. Furthermore, we found that DNA cleaved by MUS81 induces type I interferon expression in a STING-dependent manner, and initiates an innate immune response in vivo. Cytosolic DNA in tumor cells was also abrogated upon inhibition of DNA damage sensors, ATM/ATR and PARP1. In addition, genetic inhibition of Mus81 in different tumor cells lines impaired expression of cytosolic DNA and type I interferon. In summary, our data suggest that the structure-specific endonuclease MUS81 cleaves damaged nuclear DNA leading to accumulation of genomic DNA in the cytosol of tumor cells, activating immunosurveillance mechanisms. Citation Format: Samantha Ho, Stephan Gasser. The role of structure-specific endonuclease MUS81 in the induction of cytosolic DNA in tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3654. doi:10.1158/1538-7445.AM2014-3654