Abstract：
:The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like APOBEC3A and APOBEC3B have emerged as key mutation drivers in cancer. Here, we show that APOBEC3A and APOBEC3B activities impose a unique type of replication stress by inducing abasic sites at replication forks. In contrast to cells under other types of replication stress, APOBEC3A-expressing cells were selectively sensitive to ATR inhibitors (ATRi), but not to a variety of DNA replication inhibitors and DNA-damaging drugs. In proliferating cells, APOBEC3A modestly elicited ATR but not ATM. ATR inhibition in APOBEC3A-expressing cells resulted in a surge of abasic sites at replication forks, revealing an ATR-mediated negative feedback loop during replication. The surge of abasic sites upon ATR inhibition associated with increased accumulation of single-stranded DNA, a substrate of APOBEC3A, triggering an APOBEC3A-driven feed-forward loop that ultimately drove cells into replication catastrophe. In a panel of cancer cell lines, ATRi selectively induced replication catastrophe in those harboring high APOBEC3A and/or APOBEC3B activities, showing that APOBEC3A and APOBEC3B activities conferred susceptibility to ATRi. Our results define an APOBEC-driven replication stress in cancer cells that may offer an opportunity for ATR-targeted therapy. Cancer Res; 77(17); 4567-78. ©2017 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Buisson R,Lawrence MS,Benes CH,Zou Ldoi
10.1158/0008-5472.CAN-16-3389subject
Has Abstractpub_date
2017-09-01 00:00:00pages
4567-4578issue
17eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-16-3389journal_volume
77pub_type
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