DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer


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Nnenna Kanu1
1UCL Cancer Institute

Abstract

The APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types. Although many studies have documented the downstream effects of APOBEC3 activity through next-generation sequencing, less is known about their upstream regulation. We sought to identify a molecular basis for APOBEC3 expression and activation. We identified that HER2 amplification and PTEN loss promote DNA replication stress and APOBEC3 activity in vitro and correlates with APOBEC3 mutagenesis in vivo. HER2-enriched breast carcinomas, display evidence of elevated levels of replication stress associated DNA damage in vivo. Chemical and cytotoxic induction of replication stress, through aphidicolin, gemcitabine, camptothecin or hydroxyurea exposure, activate transcription of APOBEC3B via an ATR/Chk1-dependent pathway in vitro.

APOBEC3 activation can be attenuated through repression of oncogenic signalling, small molecule inhibition of receptor tyrosine kinase signalling and alleviation of replication stress through nucleoside supplementation. Our data link oncogene, loss of tumour suppressor gene and drug-induced replication stress with APOBEC3 activity, providing new insights into how cytidine deaminase-induced mutagenesis might be activated in tumourigenesis and limited therapeutically.