TY - JOUR
T1 - DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer
AU - Kanu, Nnennaya
AU - Cerone, Maria Antonietta
AU - Goh, Gerald
AU - Zalmas, Lykourgos Panagiotis
AU - Bartkova, Jirina
AU - Dietzen, Michelle
AU - McGranahan, Nicholas
AU - Rogers, Rebecca
AU - Law, Emily K.
AU - Gromova, Irina
AU - Kschischo, Maik
AU - Walton, Michael I.
AU - Rossanese, Olivia W.
AU - Bartek, Jiri
AU - Harris, Reuben S.
AU - Venkatesan, Subramanian
AU - Swanton, Charles
N1 - Publisher Copyright:
© 2016 The Author(s).
PY - 2016/9/15
Y1 - 2016/9/15
N2 - Background: 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. In this study, we sought to identify a molecular basis for APOBEC3 expression and activation. Results: HER2 amplification and PTEN loss promote DNA replication stress and APOBEC3B activity in vitro and correlate 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, activates transcription of APOBEC3B via an ATR/Chk1-dependent pathway in vitro. APOBEC3B 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. Conclusion: These data link oncogene, loss of tumour suppressor gene and drug-induced replication stress with APOBEC3B activity, providing new insights into how cytidine deaminase-induced mutagenesis might be activated in tumourigenesis and limited therapeutically.
AB - Background: 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. In this study, we sought to identify a molecular basis for APOBEC3 expression and activation. Results: HER2 amplification and PTEN loss promote DNA replication stress and APOBEC3B activity in vitro and correlate 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, activates transcription of APOBEC3B via an ATR/Chk1-dependent pathway in vitro. APOBEC3B 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. Conclusion: These data link oncogene, loss of tumour suppressor gene and drug-induced replication stress with APOBEC3B activity, providing new insights into how cytidine deaminase-induced mutagenesis might be activated in tumourigenesis and limited therapeutically.
KW - APOBEC
KW - Genomic instability
KW - Replication stress
KW - Somatic mutation
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U2 - 10.1186/s13059-016-1042-9
DO - 10.1186/s13059-016-1042-9
M3 - Article
C2 - 27634334
AN - SCOPUS:84988848343
SN - 1474-7596
VL - 17
JO - Genome biology
JF - Genome biology
IS - 1
M1 - 185
ER -