Regulation of APOBEC3 cytidine deaminase-induced mutation during cancerdevelopment

Active Project Grant Awarded Last action

Award ID
R01CA269784
Recipient
Awarding agency
Obligated
$7,143,587

Award facts

Assistance listing
93.393 Cancer Cause and Prevention Research
Completion date 74% complete
Place of performance
Burlington, VT 05401, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Apobec signature mutations (c to t and c to g substitutions in TCA and TCT trinucleotide sequences) comprise the second most abundant mutation signature in human cancers. This signature is caused by aberrant activity of several members of the apobec family of cytidine deaminases, which normally function in many cellular processes including the restriction of viruses. Recently, we found that APOBEC3A (A3A) expression is elevated in apobec-mutated breast cancer cell lines, resulting in increased cellular cytidine deaminase activity and breast cancer mutagenesis. The objectives of this proposal are to characterize newly identified components of the apobec mutation signature, determine how A3A mrna expression is upregulated in cancer, define proteasomal controls on A3A protein abundance, and characterize DNA repair pathways that limit A3A mutagenesis. AIM1 will determine the causes and consequences of A3A- and APOBEC3B-induced insertion/deletion mutations. Aim 2 will characterize the mechanisms leading to aberrant up-regulation of A3A in breast cancers by identifying the transcription factors and signaling pathways responsible for increasing A3A expression. Additionally, we will investigate the mechanism(s) leading to proteasome-dependent degradation of A3A and assess the mutagenic consequences of defective post- translational control of A3A abundance. AIM3 will characterize anti-mutagenic roles of the homologous recombination proteins BRCA1 and BRCA2 in template switch-mediated bypass of A3A-dependent abasic sites at replication forks. We will determine whether BRCA1 or BRCA2-deficiency elevates apobec-induced mutation in human cell lines and genetically define additional proteins involved in the pathway. Successful completion of these aims will enhance our understanding of A3A regulation and its role in cancer etiology. Additionally, these efforts will identify means to limit apobec-induced mutagenesis, which could provide therapeutic benefit by limiting continued tumor evolution that leads to drug resistance.

Transactions

Action Obligated Date
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Original award $471,768
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Subawards

Subrecipient Amount Awarded
Sloan-Kettering Institute For Cancer Research Regulation of APOBEC3 cytidine deaminase-induced mutation during cancer development $215,897
The Trustees Of The University Of Pennsylvania $219,244

Quick answers

Who received award R01CA269784?

R01CA269784 was awarded to University Of Vermont & State Agricultural College by National Cancer Institute (National Institutes of Health) on February 6, 2023.

How much is award R01CA269784 worth?

$7,143,587 has been obligated on R01CA269784.

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