Annexin A1 as a putative target of anti‐mutagenic action of dietary flavonoids

Abstract

Annexin A1 responds to DNA damaging agents via SUMOylation‐Ubiquitination pathways and is translocated to nuclei. Mono‐ubiquitinated annexin A1 has higher affinity for damaged DNA and promotes in vitro translesion DNA synthesis. In order to explore roles of annexin A1 in chemical mutagenesis, ultimately cancer initiation, we investigated roles of annexin A1 in mutation of the tk gene in L5178Ytk(+/−) lymphoma cells. An anti‐annexin A1 oligonucleotide, but not a scrambled oligonucleotide suppressed the MMS and As3+ induced mutation of the tk gene as judged by number of large colonies resistant to TFT. Silibinin, quercetin and genistein reduced such mutation, while flavone and flavonol were ineffective. The anti‐mutagenic flavonoids inhibited annexin A1‐dependent translesion DNA synthesis by nuclear extracts of L5178Ytk(+/−) lymphoma cells. Since silibinin, quercetin and genistein directly bound to purified mono‐ubiquitinated annexin A1 and inhibited its DNA helicase activity, we propose that nuclear annexin A1 is a putative target of dietary cancer chemopreventive flavonoids to inhibit gene mutation, ultimately cancer initiation. Supported in part by a grant from the Suzan G. Komen Foundation.