APOBEC3 upregulation drives gemcitabine resistance

Abstract

Gemcitabine is a widely used chemotherapy that interferes with tumor growth by targeting DNA replication. Understanding why many tumors are unresponsive to gemcitabine is a clinical challenge. A new study reports that upregulation of the cytidine deaminases APOBEC3C and APOBEC3D facilitates gemcitabine resistance by protecting against DNA replication stress.

Figure 1 |. The APOBEC3 family of cytidine deaminases drive cancer genome evolution and therapy resistance.

a, The APOBEC3 family of proteins consists of seven closely related paralogs located on chromosome 22. APOBEC3A, APOBEC3C, and APOBEC3H possess single zinc-dependent domains, while APOBEC3B, APOBEC3D, APOBEC3F, and APOBEC3G have two domains. Colors indicate distinct classes of catalytic domains (blue, Z1 catalytic domain; red, Z2 catalytic domain; green, Z3 catalytic domain). b, APOBEC3A and APOBEC3B enzymes are potent mutagens across numerous cancer types where they produce mutation patterns or signatures largely consisting of C>T and C>G mutations within their preferred TCA and TCT motifs. c, APOBEC3A and APOBEC3B-induced mutagenesis is proposed to promote subclonal evolution and resistance to targeted therapies.

Figure 2 |. Proposed model of APOBEC3C and APOBEC3D-mediated resistance to gemcitabine-induced replication stress.

Top, In the absence of APOBEC3C or APOBEC3D, DNA replication forks that have stalled at gemcitabine lesions fail to restart, leading to fork collapse and under-replication manifesting as RPA phosphorylation, micronucleation, and gemcitabine hypersensitivity. Bottom, APOBEC3C and APOBEC3D induction following gemcitabine treatment promotes deamination of cytosines at ssDNA exposed at stalled replication forks. Excision of the resulting uracil by UNG generates abasic sites. Recruitment of translesion DNA synthesis machinery like Rev1 and DNA Polymerase η to abasic sites enables fork restart and promotes resistance to gemcitabine-induced replication stress.