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Article ; Online: Sequence context-specific mutagenesis and base excision repair.

Donigan, Katherine A / Sweasy, Joann B

2009 Volume 48, Issue 4, Page(s) 362–368

Abstract: Base excision repair (BER) is critical for the maintenance of genome stability because it repairs at least 20,000 endogenously generated DNA lesions/cell/d. Several enzymes within the BER pathway exhibit sequence context dependency during the excision ... ...

Abstract	Base excision repair (BER) is critical for the maintenance of genome stability because it repairs at least 20,000 endogenously generated DNA lesions/cell/d. Several enzymes within the BER pathway exhibit sequence context dependency during the excision and DNA synthesis steps of repair. New evidence is emerging that germ line and tumor-associated variants of enzymes in this repair pathway exhibit sequence context dependence that is different from their ancestral counterparts. We review what is known about the ancestral and variant BER proteins within various sequence contexts. We suggest that altering the sequence context preferences of BER proteins could give rise to rare cellular variants that might have a selective advantage in response to environmental exposure or to the tumor microenvironment.
MeSH term(s)	DNA Damage ; DNA Repair ; DNA Repair Enzymes ; Humans ; Mutagenesis ; Neoplasms/etiology ; Sequence Analysis
Chemical Substances	DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2009-03-24
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.20497
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Article ; Online: The S229L colon tumor-associated variant of DNA polymerase β induces cellular transformation as a result of decreased polymerization efficiency.

Nemec, Antonia A / Murphy, Drew L / Donigan, Katherine A / Sweasy, Joann B

The Journal of biological chemistry

2014 Volume 289, Issue 20, Page(s) 13708–13716

Abstract: DNA polymerase β (Pol β) plays a key role in base excision repair (BER) by filling in small gaps that are generated after base adducts are excised from the DNA. Pol β is mutated in a large number of colorectal tumors, and these mutations may drive ... ...

Abstract	DNA polymerase β (Pol β) plays a key role in base excision repair (BER) by filling in small gaps that are generated after base adducts are excised from the DNA. Pol β is mutated in a large number of colorectal tumors, and these mutations may drive carcinogenesis. In the present study, we wished to determine whether the S229L somatic Pol β variant identified in a stage 3 colorectal tumor is a driver of carcinogenesis. We show that S229L does not possess any defects in binding to either DNA or nucleotides compared with the WT enzyme, but exhibits a significant loss of polymerization efficiency, largely due to an 8-fold decrease in the polymerization rate. S229L participates in BER, but due to its lower catalytic rate, does so more slowly than WT. Expression of S229L in mammalian cells induces the accumulation of BER intermediate substrates, chromosomal aberrations, and cellular transformation. Our results are consistent with the interpretation that S229L is a driver of carcinogenesis, likely as a consequence of its slow polymerization activity during BER in vivo.
MeSH term(s)	Animals ; Base Sequence ; Carcinogenesis/genetics ; Cell Line ; Cell Transformation, Neoplastic/genetics ; Chromosome Aberrations ; Colonic Neoplasms/enzymology ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; DNA/biosynthesis ; DNA/genetics ; DNA/metabolism ; DNA Polymerase beta/chemistry ; DNA Polymerase beta/genetics ; DNA Polymerase beta/metabolism ; DNA Repair ; Gene Expression Regulation, Enzymologic ; Genomic Instability/genetics ; Humans ; Kinetics ; Mice ; Mutation ; Neoplasm Staging ; Nucleotides/metabolism ; Protein Multimerization/genetics ; Protein Structure, Quaternary ; Protein Structure, Tertiary
Chemical Substances	Nucleotides ; DNA (9007-49-2) ; DNA Polymerase beta (EC 2.7.7.7)
Language	English
Publishing date	2014-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M114.550400
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Article ; Online: The human gastric cancer-associated DNA polymerase β variant D160N is a mutator that induces cellular transformation.

Donigan, Katherine A / Hile, Suzanne E / Eckert, Kristin A / Sweasy, Joann B

DNA repair

2012 Volume 11, Issue 4, Page(s) 381–390

Abstract: Approximately 30% of human tumors sequenced to date harbor mutations in the POLB gene that are not present in matched normal tissue. Many mutations give rise to enzymes that contain non-synonymous single amino acid substitutions, several of which have ... ...

Abstract	Approximately 30% of human tumors sequenced to date harbor mutations in the POLB gene that are not present in matched normal tissue. Many mutations give rise to enzymes that contain non-synonymous single amino acid substitutions, several of which have been found to have aberrant activity or fidelity and transform cells when expressed. The DNA Polymerase β (Pol β) variant Asp160Asn (D160N) was first identified in a gastric tumor. Expression of D160N in cells induces cellular transformation as measured by hyperproliferation, focus formation, anchorage-independent growth and invasion. Here, we show that D160N is an active mutator polymerase that induces complex mutations. Our data support the interpretation that complex mutagenesis is the underlying mechanism of the observed cellular phenotypes, all of which are linked to tumorigenesis or tumor progression.
MeSH term(s)	Amino Acid Substitution ; Animals ; Base Sequence ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; DNA/metabolism ; DNA Ligase ATP ; DNA Ligases/metabolism ; DNA Polymerase beta/genetics ; DNA Polymerase beta/metabolism ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation, Neoplastic/genetics ; Genomic Instability/genetics ; Humans ; Mice ; Molecular Sequence Data ; Mutation ; Neoplasm Invasiveness ; Phenotype ; Poly-ADP-Ribose Binding Proteins ; Stomach Neoplasms/enzymology ; Stomach Neoplasms/genetics ; Stomach Neoplasms/metabolism ; Stomach Neoplasms/pathology ; X-ray Repair Cross Complementing Protein 1 ; Xenopus Proteins
Chemical Substances	DNA-Binding Proteins ; Poly-ADP-Ribose Binding Proteins ; X-ray Repair Cross Complementing Protein 1 ; Xenopus Proteins ; DNA (9007-49-2) ; DNA Polymerase beta (EC 2.7.7.7) ; DNA Ligases (EC 6.5.1.-) ; DNA Ligase ATP (EC 6.5.1.1) ; DNA ligase III alpha protein, Xenopus (EC 6.5.1.1)
Language	English
Publishing date	2012-02-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2012.01.004
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Article ; Online: The E288K colon tumor variant of DNA polymerase β is a sequence specific mutator.

Murphy, Drew L / Donigan, Katherine A / Jaeger, Joachim / Sweasy, Joann B

Biochemistry

2012 Volume 51, Issue 26, Page(s) 5269–5275

Abstract: DNA polymerase β (pol β) is the main polymerase involved in base excision repair (BER), which is a pathway responsible for the repair of tens of thousands of DNA lesions per cell per day. Our recent efforts in sequencing colon tumors showed that 40% of ... ...

Abstract	DNA polymerase β (pol β) is the main polymerase involved in base excision repair (BER), which is a pathway responsible for the repair of tens of thousands of DNA lesions per cell per day. Our recent efforts in sequencing colon tumors showed that 40% of the tumors sequenced possessed a variant in the coding region of the POLB gene; one of these variants is E288K. Expression of the E288K variant in cells leads to an increase in the frequency of mutations at AT base pairs. In vitro, the E288K variant is as active as and binds one-base-gapped DNA with the same affinity as wild-type pol β. Single-turnover kinetic data for the E288K variant show that its mutator phenotype is specific for misincorporating opposite template A up to 6-fold more than the wild-type enzyme and that this is due to a decrease in the degree of discrimination in nucleotide binding. Molecular modeling suggests that the substitution of Lys at position 288 causes the polymerase to adopt a more open conformation, which may be disrupting the nucleotide binding pocket. This may explain the reduced degree of discrimination at the level of nucleotide binding. The enhanced mutagenesis of the E288K variant could lead to genomic instability and ultimately a malignant tumor phenotype.
MeSH term(s)	Cell Line ; Circular Dichroism ; Colonic Neoplasms/enzymology ; Colonic Neoplasms/genetics ; DNA Polymerase beta/genetics ; DNA Polymerase beta/metabolism ; Genomic Instability/genetics ; Humans ; Mutagenesis/genetics ; Mutation
Chemical Substances	DNA Polymerase beta (EC 2.7.7.7)
Language	English
Publishing date	2012-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi3003583
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Zs.A 217: Show issues

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Article ; Online: DNA polymerase β variant Ile260Met generates global gene expression changes related to cellular transformation.

Donigan, Katherine A / Tuck, David / Schulz, Vince / Sweasy, Joann B

Mutagenesis

2012 Volume 27, Issue 6, Page(s) 683–691

Abstract: Maintenance of genomic stability is essential for cellular survival. The base excision repair (BER) pathway is critical for resolution of abasic sites and damaged bases, estimated to occur 20,000 times in cells daily. DNA polymerase β (Pol β) ... ...

Abstract	Maintenance of genomic stability is essential for cellular survival. The base excision repair (BER) pathway is critical for resolution of abasic sites and damaged bases, estimated to occur 20,000 times in cells daily. DNA polymerase β (Pol β) participates in BER by filling DNA gaps that result from excision of damaged bases. Approximately 30% of human tumours express Pol β variants, many of which have altered fidelity and activity in vitro and when expressed, induce cellular transformation. The prostate tumour variant Ile260Met transforms cells and is a sequence-context-dependent mutator. To test the hypothesis that mutations induced in vivo by Ile260Met lead to cellular transformation, we characterized the genome-wide expression profile of a clone expressing Ile260Met as compared with its non-induced counterpart. Using a 1.5-fold minimum cut-off with a false discovery rate (FDR) of <0.05, 912 genes exhibit altered expression. Microarray results were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and revealed unique expression profiles in other clones. Gene Ontology (GO) clusters were analyzed using Ingenuity Pathways Analysis to identify altered gene networks and associated nodes. We determined three nodes of interest that exhibited dysfunctional regulation of downstream gene products without themselves having altered expression. One node, peroxisome proliferator-activated protein γ (PPARG), was sequenced and found to contain a coding region mutation in PPARG2 only in transformed cells. Further analysis suggests that this mutation leads to dominant negative activity of PPARG2. PPARG is a transcription factor implicated to have tumour suppressor function. This suggests that the PPARG2 mutant may have played a role in driving cellular transformation. We conclude that PPARG induces cellular transformation by a mutational mechanism.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics ; Cloning, Molecular ; DNA/genetics ; DNA Copy Number Variations ; DNA Polymerase beta/genetics ; DNA Polymerase beta/metabolism ; DNA Repair ; Gene Expression ; Genes, Tumor Suppressor ; Genomic Instability ; Mice ; Mutation ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, DNA ; Transcriptome
Chemical Substances	DNA (9007-49-2) ; DNA Polymerase beta (EC 2.7.7.7)
Language	English
Publishing date	2012-08-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	632903-2
ISSN	1464-3804 ; 0267-8357
ISSN (online)	1464-3804
ISSN	0267-8357
DOI	10.1093/mutage/ges034
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Zs.A 2189: Show issues

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Article ; Online: The steric gate of DNA polymerase ι regulates ribonucleotide incorporation and deoxyribonucleotide fidelity.

Donigan, Katherine A / McLenigan, Mary P / Yang, Wei / Goodman, Myron F / Woodgate, Roger

The Journal of biological chemistry

2014 Volume 289, Issue 13, Page(s) 9136–9145

Abstract: Accurate DNA synthesis in vivo depends on the ability of DNA polymerases to select dNTPs from a nucleotide pool dominated by NTPs. High fidelity replicative polymerases have evolved to efficiently exclude NTPs while copying long stretches of undamaged ... ...

Abstract	Accurate DNA synthesis in vivo depends on the ability of DNA polymerases to select dNTPs from a nucleotide pool dominated by NTPs. High fidelity replicative polymerases have evolved to efficiently exclude NTPs while copying long stretches of undamaged DNA. However, to bypass DNA damage, cells utilize specialized low fidelity polymerases to perform translesion DNA synthesis (TLS). Of interest is human DNA polymerase ι (pol ι), which has been implicated in TLS of oxidative and UV-induced lesions. Here, we evaluate the ability of pol ι to incorporate NTPs during DNA synthesis. pol ι incorporates and extends NTPs opposite damaged and undamaged template bases in a template-specific manner. The Y39A "steric gate" pol ι mutant is considerably more active in the presence of Mn(2+) compared with Mg(2+) and exhibits a marked increase in NTP incorporation and extension, and surprisingly, it also exhibits increased dNTP base selectivity. Our results indicate that a single residue in pol ι is able to discriminate between NTPs and dNTPs during DNA synthesis. Because wild-type pol ι incorporates NTPs in a template-specific manner, certain DNA sequences may be "at risk" for elevated mutagenesis during pol ι-dependent TLS. Molecular modeling indicates that the constricted active site of wild-type pol ι becomes more spacious in the Y39A variant. Therefore, the Y39A substitution not only permits incorporation of ribonucleotides but also causes the enzyme to favor faithful Watson-Crick base pairing over mutagenic configurations.
MeSH term(s)	Amino Acid Sequence ; Base Pairing ; Catalytic Domain ; Conserved Sequence ; DNA/biosynthesis ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; DNA Damage ; DNA Primers/genetics ; DNA-Directed DNA Polymerase/chemistry ; DNA-Directed DNA Polymerase/genetics ; DNA-Directed DNA Polymerase/metabolism ; Deoxyribonucleotides/metabolism ; Humans ; Manganese/pharmacology ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis ; Mutation ; Ribonucleotides/metabolism ; Substrate Specificity ; Tyrosine
Chemical Substances	DNA Primers ; Deoxyribonucleotides ; Ribonucleotides ; Tyrosine (42HK56048U) ; Manganese (42Z2K6ZL8P) ; DNA (9007-49-2) ; DNA polymerase iota (EC 2.7.7.-) ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
Language	English
Publishing date	2014-02-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M113.545442
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Article ; Online: Tumor-associated mutations in a conserved structural motif alter physical and biochemical properties of human RAD51 recombinase.

Chen, Jianhong / Morrical, Milagros D / Donigan, Katherine A / Weidhaas, Joanne B / Sweasy, Joann B / Averill, April M / Tomczak, Jennifer A / Morrical, Scott W

Nucleic acids research

2015 Volume 43, Issue 2, Page(s) 1098–1111

Abstract: Human RAD51 protein catalyzes DNA pairing and strand exchange reactions that are central to homologous recombination and homology-directed DNA repair. Successful recombination/repair requires the formation of a presynaptic filament of RAD51 on ssDNA. ... ...

Abstract	Human RAD51 protein catalyzes DNA pairing and strand exchange reactions that are central to homologous recombination and homology-directed DNA repair. Successful recombination/repair requires the formation of a presynaptic filament of RAD51 on ssDNA. Mutations in BRCA2 and other proteins that control RAD51 activity are associated with human cancer. Here we describe a set of mutations associated with human breast tumors that occur in a common structural motif of RAD51. Tumor-associated D149N, R150Q and G151D mutations map to a Schellman loop motif located on the surface of the RecA homology domain of RAD51. All three variants are proficient in DNA strand exchange, but G151D is slightly more sensitive to salt than wild-type (WT). Both G151D and R150Q exhibit markedly lower catalytic efficiency for adenosine triphosphate hydrolysis compared to WT. All three mutations alter the physical properties of RAD51 nucleoprotein filaments, with G151D showing the most dramatic changes. G151D forms mixed nucleoprotein filaments with WT RAD51 that have intermediate properties compared to unmixed filaments. These findings raise the possibility that mutations in RAD51 itself may contribute to genome instability in tumor cells, either directly through changes in recombinase properties, or indirectly through changes in interactions with regulatory proteins.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Amino Acid Motifs/genetics ; DNA/metabolism ; Humans ; Models, Molecular ; Mutation ; Neoplasms/genetics ; Protein Folding ; Rad51 Recombinase/chemistry ; Rad51 Recombinase/genetics ; Rad51 Recombinase/metabolism
Chemical Substances	Adenosine Triphosphate (8L70Q75FXE) ; DNA (9007-49-2) ; Rad51 Recombinase (EC 2.7.7.-)
Language	English
Publishing date	2015-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gku1337
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Zs.A 1067: Show issues

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Article ; Online: Unlocking the steric gate of DNA polymerase η leads to increased genomic instability in Saccharomyces cerevisiae.

Donigan, Katherine A / Cerritelli, Susana M / McDonald, John P / Vaisman, Alexandra / Crouch, Robert J / Woodgate, Roger

DNA repair

2015 Volume 35, Page(s) 1–12

Abstract: DNA polymerase η (pol η) is best characterized for its ability to perform accurate and efficient translesion DNA synthesis (TLS) through cyclobutane pyrimidine dimers (CPDs). To ensure accurate bypass the polymerase is not only required to select the ... ...

Abstract	DNA polymerase η (pol η) is best characterized for its ability to perform accurate and efficient translesion DNA synthesis (TLS) through cyclobutane pyrimidine dimers (CPDs). To ensure accurate bypass the polymerase is not only required to select the correct base, but also discriminate between NTPs and dNTPs. Most DNA polymerases have a conserved "steric gate" residue which functions to prevent incorporation of NMPs during DNA synthesis. Here, we demonstrate that the Phe35 residue of Saccharomyces cerevisiae pol η functions as a steric gate to limit the use of ribonucleotides during polymerization both in vitro and in vivo. Unlike the related pol ι enzyme, wild-type pol η does not readily incorporate NMPs in vitro. In contrast, a pol η F35A mutant incorporates NMPs on both damaged and undamaged DNA in vitro with a high degree of base selectivity. An S.cerevisiae strain expressing pol η F35A (rad30-F35A) that is also deficient for nucleotide excision repair (rad1Δ) and the TLS polymerase, pol ζ (rev3Δ), is extremely sensitive to UV-light. The sensitivity is due, in part, to RNase H2 activity, as an isogenic rnh201Δ strain is roughly 50-fold more UV-resistant than its RNH201(+) counterpart. Interestingly the rad1Δ rev3Δ rad30-F35A rnh201Δ strain exhibits a significant increase in the extent of spontaneous mutagenesis with a spectrum dominated by 1bp deletions at runs of template Ts. We hypothesize that the increased mutagenesis is due to rA incorporation at these sites and that the short poly rA tract is subsequently repaired in an error-prone manner by a novel repair pathway that is specifically targeted to polyribonucleotide tracks. These data indicate that under certain conditions, pol η can compete with the cell's replicases and gain access to undamaged genomic DNA. Such observations are consistent with a role for pol η in replicating common fragile sites (CFS) in human cells.
MeSH term(s)	Alanine/chemistry ; Alanine/genetics ; Amino Acid Substitution ; Base Sequence ; Conserved Sequence ; DNA Damage/genetics ; DNA Repair/genetics ; DNA Replication ; DNA, Fungal/chemistry ; DNA, Fungal/genetics ; DNA-Directed DNA Polymerase/chemistry ; DNA-Directed DNA Polymerase/genetics ; Genomic Instability ; Molecular Sequence Data ; Mutagenesis ; Mutation ; Phenylalanine/chemistry ; Phenylalanine/genetics ; Polyribonucleotides/metabolism ; Ribonucleotides/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Ultraviolet Rays
Chemical Substances	DNA, Fungal ; Polyribonucleotides ; Ribonucleotides ; Saccharomyces cerevisiae Proteins ; Phenylalanine (47E5O17Y3R) ; DNA replicase (EC 2.7.7.-) ; DNA-Directed DNA Polymerase (EC 2.7.7.7) ; Rad30 protein (EC 2.7.7.7) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2015-08-07
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2015.07.002
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Article: Crypticity and functional distribution of the membrane associated alpha-L-fucosidase of human sperm.

Venditti, Jennifer J / Donigan, Katherine A / Bean, Barry S

Molecular reproduction and development

2007 Volume 74, Issue 6, Page(s) 758–766

Abstract: Two distinctive isoforms of the enzyme alpha-L-fucosidase are found within human semen in substantial amounts, suggesting specialized functions during reproduction. The membrane-associated isozyme of human sperm cells was previously characterized ... ...

Abstract	Two distinctive isoforms of the enzyme alpha-L-fucosidase are found within human semen in substantial amounts, suggesting specialized functions during reproduction. The membrane-associated isozyme of human sperm cells was previously characterized biochemically, and here we report on its subcellular localization. Intact, detergent permeabilized, capacitated, and acrosome-reacted sperm were investigated using antifucosidase immunofluorescence, binding of the fluorescent fucosylated glycoconjugate RITC-BSA-fucose (RBF), and enzyme activity in the presence and absence of selected inhibitors. Both immunolocalization and RBF binding show that fucosidase is broadly distributed over the membrane systems of human sperm, but is relatively enriched within the equatorial segment. Upon detergent treatment or induction of acrosome reaction (AR), a portion of enzyme activity is recoverable in the supernatant, presumably associated with released remnants of the outer acrosomal membrane. Surprisingly, cell-bound enzyme activity increases sharply following permeabilization of intact sperm, representing cryptic fucosidase that is relatively stable and corresponds with strong fluorescence in the equatorial segment and other sperm membranes. These observations support the notion that the fucosidase has a role in the intimate species signature interactions between sperm and oocyte.
MeSH term(s)	Acrosome/metabolism ; Adolescent ; Adult ; Binding Sites ; Cell Membrane/metabolism ; Fucose/metabolism ; Humans ; Male ; Protein Binding ; Sperm Capacitation/physiology ; Spermatozoa/enzymology ; Spermatozoa/metabolism ; Tissue Distribution ; alpha-L-Fucosidase/metabolism
Chemical Substances	Fucose (28RYY2IV3F) ; alpha-L-Fucosidase (EC 3.2.1.51)
Language	English
Publishing date	2007-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	20321-x
ISSN	1098-2795 ; 1040-452X
ISSN (online)	1098-2795
ISSN	1040-452X
DOI	10.1002/mrd.20666
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Zs.A 2759: Show issues

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Article ; Online: Colon cancer-associated DNA polymerase β variant induces genomic instability and cellular transformation.

Nemec, Antonia A / Donigan, Katherine A / Murphy, Drew L / Jaeger, Joachim / Sweasy, Joann B

The Journal of biological chemistry

2012 Volume 287, Issue 28, Page(s) 23840–23849

Abstract: Rapidly advancing technology has resulted in the generation of the genomic sequences of several human tumors. We have identified several mutations of the DNA polymerase β (pol β) gene in human colorectal cancer. We have demonstrated that the expression ... ...

Abstract	Rapidly advancing technology has resulted in the generation of the genomic sequences of several human tumors. We have identified several mutations of the DNA polymerase β (pol β) gene in human colorectal cancer. We have demonstrated that the expression of the pol β G231D variant increased chromosomal aberrations and induced cellular transformation. The transformed phenotype persisted in the cells even once the expression of G231D was extinguished, suggesting that it resulted as a consequence of genomic instability. Biochemical analysis revealed that its catalytic rate was 140-fold slower than WT pol β, and this was a result of the decreased binding affinity of nucleotides by G231D. Residue 231 of pol β lies in close proximity to the template strand of the DNA. Molecular modeling demonstrated that the change from a small and nonpolar glycine to a negatively charged aspartate resulted in a repulsion between the template and residue 231 leading to the distortion of the dNTP binding pocket. In addition, expression of G231D was insufficient to rescue pol β-deficient cells treated with chemotherapeutic agents suggesting that these agents may be effectively used to treat tumors harboring this mutation. More importantly, this suggests that the G231D variant has impaired base excision repair. Together, these data indicate that the G231D variant plays a role in driving cancer.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Base Sequence ; Biocatalysis ; Blotting, Western ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/genetics ; Cell Transformation, Neoplastic/genetics ; Cells, Cultured ; Chromosome Aberrations ; Colonic Neoplasms/enzymology ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; DNA Polymerase beta/chemistry ; DNA Polymerase beta/genetics ; DNA Polymerase beta/metabolism ; DNA Repair ; Embryo, Mammalian/cytology ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Genomic Instability/genetics ; HEK293 Cells ; Humans ; Kinetics ; Mice ; Mice, Knockout ; Models, Molecular ; Mutation ; Protein Binding
Chemical Substances	Antineoplastic Agents ; DNA (9007-49-2) ; DNA Polymerase beta (EC 2.7.7.7)
Language	English
Publishing date	2012-05-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.362111
Database	MEDical Literature Analysis and Retrieval System OnLINE

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