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William L. Brown
University of Minnesota
Molecular biologyCytosine deaminaseAPOBEC3GDNABiology
59Publications
23H-index
2,860Citations
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Publications 58
Newest
#1Jennifer L. McCannH-Index: 8
Last. Reuben S. HarrisH-Index: 62
view all 5 authors...
Although CRISPR/Cas9 technology has created a renaissance in genome engineering, particularly for gene knockout generation, methods to introduce precise single base changes are also highly desirable. The covalent fusion of a DNA-editing enzyme such as APOBEC to a Cas9 nickase complex has heightened hopes for such precision genome engineering. However, current cytosine base editors are prone to undesirable off-target mutations, including, most frequently, target-adjacent mutations. Here, we repor...
1 CitationsSource
#1Reuben S. Harris (HHMI: Howard Hughes Medical Institute)H-Index: 62
#1Artur A. Serebrenik (UMN: University of Minnesota)H-Index: 5
Last. Matthew J. Maurer (Mayo Clinic)H-Index: 39
view all 17 authors...
Purpose: Clear cell ovarian carcinoma (CCOC) is an aggressive disease that often demonstrates resistance to standard chemotherapies. Approximately 25% of CCOC show a strong APOBEC mutation signature. Here, we determine which APOBEC3 enzymes are expressed in CCOC, establish clinical correlates, and identify a new biomarker for detection and intervention. Experimental Design: APOBEC3 expression was analyzed by immunohistochemistry and RT-qPCR in a pilot set of CCOC specimens (n=9 tumors). The immu...
2 CitationsSource
#1Daniel J. Salamango (UMN: University of Minnesota)H-Index: 8
#2Terumasa IkedaH-Index: 10
Last. Reuben S. HarrisH-Index: 62
view all 10 authors...
Summary HIV-1 Vif hijacks a cellular ubiquitin ligase complex to degrade antiviral APOBEC3 enzymes and PP2A phosphatase regulators (PPP2R5A–E). APOBEC3 counteraction is essential for viral pathogenesis. However, Vif also functions through an unknown mechanism to induce G2 cell cycle arrest. Here, deep mutagenesis is used to define the Vif surface required for PPP2R5 degradation and isolate a panel of separation-of-function mutants (PPP2R5 degradation-deficient and APOBEC3G degradation-proficient...
6 CitationsSource
#1Artur A. Serebrenik (UMN: University of Minnesota)H-Index: 5
#2Gabriel J. Starrett (UMN: University of Minnesota)H-Index: 18
Last. Reuben S. Harris (UMN: University of Minnesota)H-Index: 62
view all 9 authors...
Human cells express up to 9 active DNA cytosine deaminases with functions in adaptive and innate immunity. Many cancers manifest an APOBEC mutation signature and APOBEC3B (A3B) is likely the main enzyme responsible. Although significant numbers of APOBEC signature mutations accumulate in tumor genomes, the majority of APOBEC-catalyzed uracil lesions are probably counteracted in an error-free manner by the uracil base excision repair pathway. Here, we show that A3B-expressing cells can be selecti...
1 CitationsSource
#1William L. Brown (UMN: University of Minnesota)H-Index: 23
#2Emily K. Law (UMN: University of Minnesota)H-Index: 12
Last. Reuben S. HarrisH-Index: 62
view all 11 authors...
The DNA cytosine deaminase APOBEC3B (A3B) is normally an antiviral factor in the innate immune response. However, A3B has been implicated in cancer mutagenesis, particularly in solid tumors of the bladder, breast, cervix, head/neck, and lung. Here, we report data on the generation and characterization of a rabbit monoclonal antibody (mAb) for human A3B. One mAb, 5210-87-13, demonstrates utility in multiple applications, including ELISA, immunoblot, immunofluorescence microscopy, and immunohistoc...
2 CitationsSource
#1Jennifer L. McCannH-Index: 8
#2Madeline M. Klein (UMN: University of Minnesota)H-Index: 1
Last. Reuben S. HarrisH-Index: 62
view all 7 authors...
: Apolipoprotein B mRNA editing enzyme catalytic subunit-like protein 3B (APOBEC3B or A3B), as other APOBEC3 members, is a single-stranded (ss)DNA cytosine deaminase with antiviral activity. A3B is also overexpressed in multiple tumor types, such as carcinomas of the bladder, cervix, lung, head/neck, and breast. A3B generates both dispersed and clustered C-to-T and C-to-G mutations in intrinsically preferred trinucleotide motifs (TCA/TCG/TCT). A3B-catalyzed mutations are likely to promote tumor ...
Source
#1Terumasa IkedaH-Index: 10
#2Amy M. MolanH-Index: 3
Last. Reuben S. HarrisH-Index: 62
view all 7 authors...
HIV-1 replication in CD4-positive T lymphocytes requires counteraction of multiple different innate antiviral mechanisms. Macrophage cells are also thought to provide a reservoir for HIV-1 replication but less is known in this cell type about virus restriction and counteraction mechanisms. Many studies have combined to demonstrate roles for APOBEC3D, APOBEC3F, APOBEC3G and APOBEC3H in HIV-1 restriction and mutation in CD4-positive T lymphocytes, whereas the APOBEC enzymes involved in HIV-1 restr...
Source
#1Michael A. Carpenter (UMN: University of Minnesota)H-Index: 11
#2Emily K. Law (UMN: University of Minnesota)H-Index: 12
Last. Reuben S. Harris (UMN: University of Minnesota)H-Index: 62
view all 5 authors...
Abstract A major concern of CRISPR and related genome engineering technologies is off-target mutagenesis from prolonged exposure to Cas9 and related editing enzymes. To help mitigate this concern we added a loxP site to the 3′-LTR of an HIV-based lentiviral vector capable of expressing Cas9/gRNA complexes in a wide variety of mammalian cell types. Transduction of susceptible target cells yields an integrated provirus that expresses the desired Cas9/gRNA complex. The reverse transcription process...
5 CitationsSource
#1A. St MartinH-Index: 1
Last. Reuben S. HarrisH-Index: 62
view all 6 authors...
The prospect of introducing a single C-to-T change at a specific genomic location has become feasible with APOBEC-Cas9 editing technologies. We present a panel of eGFP reporters for quantification and optimization of single base editing by APOBEC-Cas9 editosomes. Reporter utility is demonstrated by comparing activities of seven human APOBEC3 enzymes and rat APOBEC1 (BE3). APOBEC3A and RNA binding-defective variants of APOBEC3B and APOBEC3H display the highest single base editing efficiencies. AP...
1 CitationsSource
#1William L. Brown (UMN: University of Minnesota)H-Index: 23
#2Emily K. Law (HHMI: Howard Hughes Medical Institute)H-Index: 1
Last. Reuben S. Harris (HHMI: Howard Hughes Medical Institute)H-Index: 1
view all 11 authors...
The DNA cytosine deaminase APOBEC3B (A3B) is normally an antiviral factor in the innate immune response. However, A3B has been implicated in cancer mutagenesis, particularly in solid tumors of the bladder, breast, cervix, head/neck, and lung. Here, we report data on the generation and characterization of a rabbit monoclonal antibody (mAb) for human A3B through a series of immunoblot, immunofluorescence microscopy, and immunohistochemistry experiments. Positive results indicate that one mAb, 5210...
1 CitationsSource
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