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PROJECT 3 – STRUCTURAL BIOLOGY OF DNA DEAMINASES IN BREAST CANCER
ABSTRACT
The hallmark activity of the APOBEC family of enzymes is deamination of cytosines to uracils (C-to-U) in
single-stranded (ss)DNA. This editing activity normally functions in the innate immune response by contributing
to virus and transposon restriction. However, recent studies by our labs and many others strongly indicate that
APOBEC3B (A3B) is a major source of genomic mutations that drive the progression of multiple human
cancers and the development of drug resistance. This finding – that a cellular enzyme actively introduces
mutations in cancer – is in stark contrast to a more conventional view, in which mutations in cancer are caused
by DNA damage from exogenous sources or errors introduced during DNA replication or repair. Because A3B
is not an essential enzyme for life, it is a promising target for anti-cancer therapies. Thus, our Program's
overarching hypothesis is that A3B inhibition, as an adjuvant to primary treatment options, will help to prevent
detrimental mutation-driven outcomes such as drug resistance and metastasis. However, despite its strong
relevance to cancer as a potential therapeutic target, it is not fully known how A3B engages ssDNA substrates,
how it achieves high selectivity for ssDNA over RNA, or how its DNA deaminase activity is regulated in cells.
Moreover, it is not known how related enzymes such as APOBEC3H (A3H) and APOBEC3F (A3F) with
different compositions of ssDNA-binding residues engage similar target sequences. In Project 3, we have
started to address these issues by solving multiple A3B catalytic domain crystal structures and, recently,
achieving co-crystal structures of ssDNA bound to a variant of the A3B catalytic domain as well as to the
related enzyme APOBEC3A (A3A). Aim 1 will build on this knowledge to further delineate the global ssDNA
binding mechanism of A3B and A3H. Aim 2 will examine the local dinucleotide targeting mechanism and
possible modes of inhibition of the APOBEC family of enzymes. Our goals are to gain deeper mechanistic
understandings of the pathogenic APOBEC-mediated ssDNA cytosine deamination process and to establish a
solid foundation for future development of APOBEC inhibitors for cancer therapies. These studies will propel
our Program toward achieving its long-term goal of inhibiting APOBEC mutagenesis in breast cancer, thereby
slowing tumor evolution and improving overall therapeutic outcomes for patients.
Status | Active |
---|---|
Effective start/end date | 8/1/23 → 7/31/24 |
Funding
- National Cancer Institute: $351,914.00
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Projects
- 1 Active
-
APOBEC MUTAGENESIS IN BREAST CANCER
Aihara, H., Amaro, R. E., Carpenter, M. A., Harki, D. A., Harris, R., Li, M., Yee, D., Harris, R. R. S., Harki, D. D. A., Yee, D. D., Aihara, H. & Amaro, R. R. E.
8/9/19 → 7/31/24
Project: Research project