A Humanized Yeast Phenomic Model of Deoxycytidine Kinase to Predict Genetic Buffering of Nucleoside Analog Cytotoxicity
Abstract
:1. Introduction
2. Materials and Methods
2.1. Strains, Media, and Drugs
2.2. Quantitative High Throughput Cell Array Phenotyping (Q-HTCP)
2.3. Quantification of Drug–Gene Interaction
- Di = concentration (dose) of gemcitabine or cytarabine;
- Ri = observed mean growth parameter for parental reference strain at Di;
- Yi = observed growth parameter for the YKO/KD mutant strain at Di;
- Ki = Yi − Ri, the difference in growth parameter between the YKO/KD mutant (Yi) and reference (Ri) at Di;
- K0 = Y0 − R0, the effect of gene KO/KD on the observed phenotype in the absence of gemcitabine or cytarabine—this value is annotated as ‘shift’ and is subtracted from all Ki to obtain Li;
- Li = Ki − K0, the interaction between (specific influence of) the KO/KD mutation on gemcitabine or cytarabine response, at Di;
- (1)
- Compute the average value of the 768 reference cultures (Ri) at each dose (Di):
- (2)
- Assign Yi max (defined above) if growth curve is observed at D0, but not at Di, or if observed Yi is greater than Yi max.
- (3)
- Calculate Ki = Yi − Ri.
- (4)
- Calculate Li = Ki − K0
- (5)
- Fit data by linear regression (least squares): Li = A + B*Di
- (6)
- Compute the interaction value ‘INT’ at the max dose: INT = Li-max = A + B*Dmax
- (7)
- Calculate the mean and standard deviation of interaction scores for reference strains, mean(REFINT) and SD(REFINT); mean(REFINT) is expected to be approximately zero, with SD(REFINT) primarily useful for standardizing against variance (Additional File 1, Tables S2–S5; Additional Files 3–4).
- (8)
- Calculate interaction z-scores:z-score(YKOINT) = (YKOINT − mean(REFINT))/SD(REFINT)z-score(YKOINT) > 2 for L or < −2 for K are referred to as gene deletion enhancers of gemcitabine or cytarabine cytotoxicity, and conversely, L interaction score < −2 or K interaction scores >2 are considered gene deletion suppressors. Due to the fact that the CPP distributions for KD strains were different from the reference strain, we used the mean and standard deviation from the KD plates only as a conservative measure of variance where z-score(KDINT) = (KDINT – mean(KDINT))/SD(KDINT).
2.4. Recursive Expectation-Maximization Clustering (REMc) and Heatmap Generation
2.5. Gene Ontology Term Finder (GTF)
2.6. Gene Ontology Term Averaging (GTA) Analysis
- Calculate the average and SD for interaction values of all genes in a GO term.
- Filter results to obtain terms having GTA value greater than 2 or less than −2.
- Obtain GTA scores defined as |GTA value| - gtaSD; filter for GTA score > 2.
2.7. Prediction of Human Homologs that Influence Tumor Response to Gemcitabine or Cytarabine
3. Results
3.1. Quantitative Phenomic Characterization of Differential Gene–Drug Interaction
3.2. Functional Analysis of Gene Interaction Modules
4. Functions that Respond to Gemcitabine and Cytarabine Similarly
4.1. Genetic Modules that Buffer Cytotoxicity of Both Gemcitabine and Cytarabine
4.2. DNA Integrity Checkpoint and Repair-Related Complexes
yGene | hGene | H | Drug | Cluster | Tissue | Gem K | Cyt K | Gem L | Cyt L | Ref | Description (Human) |
---|---|---|---|---|---|---|---|---|---|---|---|
NAM7 | HELZ | 2 | Cyt | 1-0-14 | L | −6.5 | −16.7 | 1.1 | 13.6 | [66,67,68,69] | helicase with zinc finger |
NAM7 | HELZ2 | 2 | Cyt | 1-0-14 | A, H | −6.5 | −16.7 | 1.1 | 13.6 | helicase with zinc finger 2 | |
NAM7 | UPF1 | 2 | Cyt | 1-0-14 | L | −6.5 | −16.7 | 1.1 | 13.6 | [70,71,72] | UPF1, RNA helicase and ATPase |
PTC1 | PPM1E | 2 | Both | 1-0-14 | L | −8.8 | −12.7 | 7.9 | 15.7 | [73] | protein phosphatase, Mg2+/Mn2+ dependent 1E |
PTC1 | PPM1L | 2 | Both | 1-0-14 | A, H | −8.8 | −12.7 | 7.9 | 15.7 | [74] | protein phosphatase, Mg2+/Mn2+ dependent 1L |
RAD24 | RAD17 | 1 | Gem | 1-0-14 | H, L | −7.4 | −27.6 | 14.2 | 8.3 | [75,76,77,78,79] | RAD17 checkpoint clamp loader component |
SGS1 | RECQL5 | 2 | Cyt | 1-0-14 | L | −8.4 | −33.4 | 3.4 | 19.3 | [61,62] | RecQ like helicase 5 |
KTI11_2 | DPH3 | 1 | Cyt | 1-0-14 | H | −7.7 | −10.3 | 6.5 | 9.1 | [80,81,82] | diphthamide biosynthesis 3 |
BIM1_2 | MAPRE2 | 2 | Gem | 1-0-14 | A | −7.7 | −15.4 | 16.0 | 20.0 | [83] | microtubule associated protein RP/EB family member 2 |
BIM1_2 | MAPRE2 | 2 | Both | 1-0-14 | L | −7.7 | −15.4 | 16.0 | 20.0 | [83] | microtubule associated protein RP/EB family member 2 |
BIM1_2 | MAPRE3 | 2 | Gem | 1-0-14 | A | −7.7 | −15.4 | 16.0 | 20.0 | [84] | microtubule associated protein RP/EB family member 3 |
ASF1 | ASF1B | 2 | Cyt | 2-0.16-1 | L | −6.1 | −9.5 | 4.1 | 8.3 | [85] | anti-silencing function 1B histone chaperone |
AVL9 | AVL9 | 1 | Cyt | 2-0.16-1 | H | −4.3 | −2.5 | 0.2 | 2.9 | [86,87,88] | AVL9 cell migration associated |
PMR1 | ATP1A1 | 2 | Cyt | 2-0.16-1 | A, H | −3.8 | −9.8 | 3.6 | 10.1 | [89] | ATPase Na+/K+ transporting subunit α 1 |
PMR1 | ATP1A2 | 2 | Gem | 2-0.16-1 | A | −3.8 | −9.8 | 3.6 | 10.1 | [90] | ATPase Na+/K+ transporting subunit α 2 |
PMR1 | ATP1A3 | 2 | Cyt | 2-0.16-1 | L | −3.8 | −9.8 | 3.6 | 10.1 | ATPase Na+/K+ transporting subunit α 3 | |
PMR1 | ATP1A4 | 2 | Gem | 2-0.16-1 | A | −3.8 | −9.8 | 3.6 | 10.1 | ATPase Na+/K+ transporting subunit α 4 | |
PMR1 | ATP1A4 | 2 | Both | 2-0.16-1 | H | −3.8 | −9.8 | 3.6 | 10.1 | ATPase Na+/K+ transporting subunit α 4 | |
PMR1 | ATP2C1 | 2 | Cyt | 2-0.16-1 | A | −3.8 | −9.8 | 3.6 | 10.1 | [91,92] | ATPase secretory pathway Ca2+ transporting 1 |
PMR1 | ATP2C1 | 2 | Both | 2-0.16-1 | H | −3.8 | −9.8 | 3.6 | 10.1 | [91,92] | ATPase secretory pathway Ca2+ transporting 1 |
TOP3 | TOP3A | 2 | Cyt | 2-0.16-1 | L | −5.2 | −4.0 | 3.3 | 3.4 | [63,64,65] | DNA topoisomerase III α |
VPS21 | RAB21 | 3 | Cyt | 2-0.16-1 | A, H | −7.2 | −4.1 | −0.4 | 2.4 | [93,94] | RAB21, member RAS oncogene family |
VPS21 | RAB22A | 3 | Gem | 2-0.16-1 | A | −7.2 | −4.1 | −0.4 | 2.4 | [95,96,97] | RAB22A, member RAS oncogene family |
ACB1_2 | ACBD4 | 2 | Gem | 2-0.16-1 | H | −5.4 | −4.8 | 4.5 | 0.6 | [98,99] | acyl-CoA binding domain containing 4 |
ACB1_2 | ACBD5 | 2 | Cyt | 2-0.16-1 | H | −5.4 | −4.8 | 4.5 | 0.6 | [100] | acyl-CoA binding domain containing 5 |
ACB1_2 | DBI | 2 | Cyt | 2-0.16-1 | A, H | −5.4 | −4.8 | 4.5 | 0.6 | [101,102,103] | diazepam binding inhibitor, acyl-CoA binding protein |
CPR3 | PPIA | 3 | Cyt | 2-0.8-1 | A, H | 2.1 | 1.6 | −4.1 | −2.8 | [104,105,106] | peptidylprolyl isomerase A |
CPR3 | RGPD4 | 3 | Gem | 2-0.8-1 | A | 2.1 | 1.6 | −4.1 | −2.8 | RANBP2-like and GRIP domain containing 4 | |
ELO3 | ELOVL1 | 3 | Both | 2-0.8-1 | L | 2.2 | 1.3 | −3.4 | −4.0 | [107,108] | ELOVL fatty acid elongase 1 |
ELO3 | ELOVL2 | 3 | Cyt | 2-0.8-1 | H | 2.2 | 1.3 | −3.4 | −4.0 | [109] | ELOVL fatty acid elongase 2 |
ELO3 | ELOVL4 | 3 | Cyt | 2-0.8-1 | H | 2.2 | 1.3 | −3.4 | −4.0 | ELOVL fatty acid elongase 4 | |
ELO3 | ELOVL5 | 3 | Cyt | 2-0.8-1 | H | 2.2 | 1.3 | −3.4 | −4.0 | ELOVL fatty acid elongase 5 | |
ELO3 | ELOVL6 | 3 | Both | 2-0.8-1 | A, L | 2.2 | 1.3 | −3.4 | −4.0 | [110,111] | ELOVL fatty acid elongase 6 |
MDL2 | ABCB10 | 3 | Gem | 2-0.8-1 | H | 2.5 | 1.5 | −3.0 | −3.0 | [112] | ATP binding cassette subfamily B member 10 |
MDL2 | TAP1 | 3 | Cyt | 2-0.8-1 | L | 2.5 | 1.5 | −3.0 | −3.0 | transporter 1, ATP binding cassette subfamily B member | |
PIF1 | PIF1 | 2 | Gem | 2-0.8-1 | A | 2.2 | 1.5 | −4.5 | −3.4 | [113] | PIF1 5’-to-3’ DNA helicase |
RPS1B | RPS3A | 1 | Both | 2-0.8-1 | A | 2.3 | 0.9 | −3.9 | −2.3 | [114,115] | ribosomal protein S3A |
SAC3 | MCM3AP | 2 | Gem | 2-0.8-1 | H | 2.2 | 1.5 | −5.2 | −3.8 | [116] | minichromosome maintenance complex component 3 associated protein |
SAC3 | SAC3D1 | 2 | Cyt | 2-0.8-1 | H | 2.2 | 1.5 | −5.2 | −3.8 | [117,118] | SAC3 domain containing 1 |
YTA7 | ATAD2 | 2 | Both | 2-0.8-1 | A, H | 1.8 | 1.0 | −6.0 | −3.6 | [119,120,121,122,123,124,125] | ATPase family, AAA domain containing 2 |
YTA7 | ATAD2B | 2 | Both | 2-0.8-1 | H | 1.8 | 1.0 | −6.0 | −3.6 | ATPase family, AAA domain containing 2B |
4.3. Positive Regulation of DNA-Dependent DNA Replication Initiation
4.4. Endosomal Transport and Related Processes
4.5. ‘Non-GO-enriched’ Homolog Pairs with Corresponding UES and Deletion Enhancement
4.6. Deletion Suppression of Toxicity for Both Nucleosides
5. Gemcitabine-Specific Gene Interaction Modules
5.1. Gemcitabine-Specific Gene Deletion Enhancement
yGene | hGene | H | Drug | Cluster | Tissue | Gem_K | Cyt_K | Gem_L | Cyt_L | Ref | Description_Human |
---|---|---|---|---|---|---|---|---|---|---|---|
CLB5 | CCNA1 | 3 | Gem | 1-0-0 | L | −3.5 | 1.4 | 5.4 | −0.1 | [157] | cyclin A1 |
HDA1 | HDAC5 | 2 | Cyt | 1-0-0 | L | −6.4 | −2.6 | 5.0 | 2.2 | [158] | histone deacetylase 5 |
HDA1 | HDAC6 | 2 | Cyt | 1-0-0 | L | −6.4 | −2.6 | 5.0 | 2.2 | [99,159,160,161,162,163,164,165] | histone deacetylase 6 |
HSE1 | TOM1 | 2 | Gem | 1-0-0 | A | −3.3 | 1.2 | 6.5 | 0.0 | target of myb1 membrane trafficking protein | |
HSE1 | TOM1L2 | 2 | Gem | 1-0-0 | A | −3.3 | 1.2 | 6.5 | 0.0 | [151] | target of myb1 like 2 membrane trafficking protein |
NMA1 | NMNAT1 | 3 | Cyt | 1-0-0 | H | −4.6 | −2.0 | 4.2 | 2.5 | [166] | nicotinamide nucleotide adenylyltransferase 1 |
NMA1 | NMNAT2 | 3 | Both | 1-0-0 | A | −4.6 | −2.0 | 4.2 | 2.5 | [167] | nicotinamide nucleotide adenylyltransferase 2 |
NMA1 | NMNAT2 | 3 | Cyt | 1-0-0 | L | −4.6 | −2.0 | 4.2 | 2.5 | [167] | nicotinamide nucleotide adenylyltransferase 2 |
NMA1 | NMNAT3 | 3 | Cyt | 1-0-0 | L | −4.6 | −2.0 | 4.2 | 2.5 | nicotinamide nucleotide adenylyltransferase 3 | |
RAD54 | ATRX | 2 | Gem | 1-0-0 | L | −4.9 | −0.9 | 4.5 | 3.9 | [168] | ATRX, chromatin remodeler |
RAD54 | RAD54B | 2 | Cyt | 1-0-0 | L | −4.9 | −0.9 | 4.5 | 3.9 | RAD54 homolog B | |
RAD54 | RAD54L | 2 | Cyt | 1-0-0 | L | −4.9 | −0.9 | 4.5 | 3.9 | RAD54 like | |
SCS2 | VAPB | 3 | Gem | 1-0-0 | A, H, L | −4.3 | −0.2 | 3.8 | 1.4 | [100,169] | VAMP associated protein B and C |
VPS30 | BECN1 | 2 | Gem | 1-0-0 | A | −5.9 | −2.0 | 2.4 | 2.6 | [170] | beclin 1 |
VPS30 | BECN1 | 2 | Cyt | 1-0-0 | H | −5.9 | −2.0 | 2.4 | 2.6 | [170] | beclin 1 |
DID4_2 | CHMP2A | 2 | Gem | 1-0-0 | A | −6.1 | −1.2 | 5.2 | 1.8 | [171] | charged multivesicular body protein 2A |
DID4_2 | CHMP2B | 2 | Gem | 1-0-0 | A, H | −6.1 | −1.2 | 5.2 | 1.8 | [172,173] | charged multivesicular body protein 2B |
YPT32 | RAB2A | 3 | Gem | 1-0-0 | A | −4.4 | 0.3 | 5.0 | −1.8 | [174] | RAB2A, member RAS oncogene family |
YPT32 | RAB2B | 3 | Gem | 1-0-0 | L | −4.4 | 0.3 | 5.0 | −1.8 | [175] | RAB2B, member RAS oncogene family |
KEX2 | PCSK1 | 2 | Gem | 1-0-10 | A, L | −7.8 | −0.3 | 15.4 | −0.9 | [176] | proprotein convertase subtilisin/kexin type 1 |
KEX2 | PCSK2 | 2 | Gem | 1-0-10 | L | −7.8 | −0.3 | 15.4 | −0.9 | [177] | proprotein convertase subtilisin/kexin type 2 |
KEX2 | PCSK5 | 2 | Gem | 1-0-10 | A | −7.8 | −0.3 | 15.4 | −0.9 | [177,178] | proprotein convertase subtilisin/kexin type 5 |
KEX2 | PCSK7 | 2 | Gem | 1-0-10 | A | −7.8 | −0.3 | 15.4 | −0.9 | [177,179] | proprotein convertase subtilisin/kexin type 7 |
PEP12 | STX12 | 2 | Both | 1-0-10 | A | −8.0 | −16.1 | 13.6 | 5.3 | [180,181] | syntaxin 12 |
PEP12 | STX12 | 2 | Cyt | 1-0-10 | H | −8.0 | −16.1 | 13.6 | 5.3 | [180,181] | syntaxin 12 |
VPS27 | WDFY1 | 2 | Gem | 1-0-10 | L | −8.1 | −9.1 | 14.3 | 5.2 | [149,150] | WD repeat and FYVE domain containing 1 |
VPS41 | VPS41 | 1 | Cyt | 1-0-10 | H | −6.5 | −0.9 | 14.0 | 4.0 | [148] | VPS41, HOPS complex subunit |
VPS8 | VPS8 | 1 | Gem | 1-0-10 | L | −8.5 | −12.3 | 14.4 | 3.5 | [152] | VPS8, CORVET complex subunit |
VAM6_2 | VPS39 | 2 | Cyt | 1-0-10 | H | −8.0 | −2.8 | 13.9 | 4.0 | [152] | VPS39, HOPS complex subunit |
DID4_1 | CHMP2A | 2 | Both | 1-0-10 | A | −8.0 | −12.3 | 14.5 | 8.2 | [171] | charged multivesicular body protein 2A |
DID4_1 | CHMP2A | 2 | Cyt | 1-0-10 | H | −8.0 | −12.3 | 14.5 | 8.2 | [171] | charged multivesicular body protein 2A |
DID4_1 | CHMP2B | 2 | Gem | 1-0-10 | A, H | −8.0 | −12.3 | 14.5 | 8.2 | [172,173] | charged multivesicular body protein 2B |
FKH2 | FOXG1 | 3 | Cyt | 2-0.2-1 | A, L | −9.7 | −2.1 | 19.7 | 5.1 | [134] | forkhead box G1 |
FKH2 | FOXH1 | 3 | Gem | 2-0.2-1 | H | −9.7 | −2.1 | 19.7 | 5.1 | [137] | forkhead box H1 |
FKH2 | FOXJ1 | 3 | Cyt | 2-0.2-1 | A, H | −9.7 | −2.1 | 19.7 | 5.1 | [133] | forkhead box J1 |
FKH2 | FOXJ3 | 3 | Cyt | 2-0.2-1 | L | −9.7 | −2.1 | 19.7 | 5.1 | [135,136] | forkhead box J3 |
YNK1 | NME3 | 2 | Gem | 2-0.2-1 | H | −9.3 | 1.0 | 20.0 | −4.0 | NME/NM23 nucleoside diphosphate kinase 3 | |
YNK1 | NME4 | 2 | Cyt | 2-0.2-1 | A, L | −9.3 | 1.0 | 20.0 | −4.0 | NME/NM23 nucleoside diphosphate kinase 4 | |
YNK1 | NME5 | 2 | Gem | 2-0.2-1 | A | −9.3 | 1.0 | 20.0 | −4.0 | [182] | NME/NM23 family member 5 |
YNK1 | NME6 | 2 | Cyt | 2-0.2-1 | L | −9.3 | 1.0 | 20.0 | −4.0 | NME/NM23 nucleoside diphosphate kinase 6 | |
YNK1 | NME7 | 2 | Cyt | 2-0.2-1 | A, H | −9.3 | 1.0 | 20.0 | −4.0 | NME/NM23 family member 7 | |
ALD6 | ALDH1A1 | 3 | Cyt | 1-0-7 | L | 1.3 | 1.7 | −2.4 | −3.5 | [183,184,185] | aldehyde dehydrogenase 1 family member A1 |
ALD6 | ALDH1A2 | 3 | Cyt | 1-0-7 | A, H | 1.3 | 1.7 | −2.4 | −3.5 | aldehyde dehydrogenase 1 family member A2 | |
ALD6 | ALDH1B1 | 3 | Gem | 1-0-7 | L | 1.3 | 1.7 | −2.4 | −3.5 | [185] | aldehyde dehydrogenase 1 family member B1 |
ALD6 | ALDH7A1 | 3 | Cyt | 1-0-7 | A | 1.3 | 1.7 | −2.4 | −3.5 | [185] | aldehyde dehydrogenase 7 family member A1 |
CKA2 | CSNK2A1 | 2 | Gem | 1-0-7 | A | 1.2 | −0.2 | −2.5 | −1.5 | [186,187,188,189,190,191,192,193] | casein kinase 2 α 1 |
CKA2 | CSNK2A2 | 2 | Gem | 1-0-7 | A, L | 1.2 | −0.2 | −2.5 | −1.5 | [186,187,188,189,190,191,192,193] | casein kinase 2 α 2 |
CLB2 | CCNA2 | 3 | Gem | 1-0-7 | L | 2.0 | 0.4 | −2.2 | 0.6 | [194,195,196,197] | cyclin A2 |
CLB2 | CCNB1 | 3 | Gem | 1-0-7 | L | 2.0 | 0.4 | −2.2 | 0.6 | [194,195,196,197] | cyclin B1 |
EFT2 | EEF2 | 3 | Gem | 1-0-7 | A | 0.9 | 0.8 | −2.4 | −1.8 | [198] | eukaryotic translation elongation factor 2 |
EFT2 | EFTUD2 | 3 | Gem | 1-0-7 | A | 0.9 | 0.8 | −2.4 | −1.8 | [199] | elongation factor Tu GTP binding domain containing 2 |
OLA1 | OLA1 | 1 | Gem | 1-0-7 | A | 1.0 | 0.8 | −2.6 | −3.0 | [200,201,202] | Obg like ATPase 1 |
OLA1 | OLA1 | 1 | Cyt | 1-0-7 | H | 1.0 | 0.8 | −2.6 | −3.0 | [200,201,202] | Obg like ATPase 1 |
RPA49 | POLR1E | 1 | Gem | 1-0-7 | A, L | 1.8 | −0.9 | −2.6 | 0.6 | [203,204,205,206] | RNA polymerase I subunit E |
SKY1 | SRPK1 | 2 | Gem | 1-0-7 | A, L | 0.8 | −0.6 | −2.1 | −1.3 | [207] | SRSF protein kinase 1 |
SNC2 | VAMP8 | 3 | Gem | 1-0-7 | L | 1.4 | 0.1 | −2.3 | −0.6 | [208,209] | vesicle associated membrane protein 8 |
TOP1 | TOP1 | 2 | Gem | 1-0-7 | A, L | 1.3 | 0.3 | −3.1 | −3.9 | [210] | DNA topoisomerase I |
TOP1 | TOP1MT | 2 | Both | 1-0-7 | A, H, L | 1.3 | 0.3 | −3.1 | −3.9 | DNA topoisomerase I mitochondrial | |
YPT6 | RAB34 | 2 | Gem | 1-0-7 | A, L | 1.4 | 1.1 | −2.1 | 1.7 | [211,212,213] | RAB34, member RAS oncogene family |
RPP2B | RPLP2 | 2 | Gem | 2-0.8-0 | A | 1.7 | 0.2 | −5.3 | −2.8 | [214] | ribosomal protein lateral stalk subunit P2 |
YGR054W | EIF2A | 1 | Gem | 2-0.8-0 | A | 1.8 | 0.2 | −4.1 | −1.0 | [215] | eukaryotic translation initiation factor 2A |
5.2. Autophagy Related Processes
5.3. Histone Modification and Chromatin Remodeling
5.4. Peptidyl–Tyrosine Dephosphorylation
5.5. Elongator Holoenzyme Complex and Protein Urmylation
5.6. Gemcitabine-Buffering by Non-GO-Enriched Yeast-Human Homologs
5.7. Gemcitabine-Specific Gene Deletion Suppression
5.8. Correlation of Gemcitabine-Specific Gene Deletion Suppression with OES in Cancer Cells
6. Cytarabine-Specific Gene Interaction Modules
6.1. Cytarabine-Specific Gene Deletion Enhancement
yGene | hGene | H | Drug | Cluster | Tissue | Gem_K | Cyt_K | Gem_L | Cyt_L | Ref | Description_Human |
---|---|---|---|---|---|---|---|---|---|---|---|
CCH1 | CACNA1A | 2 | Cyt | 1-0-9 | A, L | 0.2 | −4.5 | 0.5 | 5.5 | [274] | calcium voltage-gated channel subunit alpha1 A |
CCH1 | CACNA1B | 2 | Cyt | 1-0-9 | A, L | 0.2 | −4.5 | 0.5 | 5.5 | [274] | calcium voltage-gated channel subunit alpha1 B |
CCH1 | CACNA1C | 2 | Cyt | 1-0-9 | A, H, L | 0.2 | −4.5 | 0.5 | 5.5 | [274] | calcium voltage-gated channel subunit alpha1 C |
CCH1 | CACNA1E | 2 | Cyt | 1-0-9 | A, L | 0.2 | −4.5 | 0.5 | 5.5 | [274] | calcium voltage-gated channel subunit alpha1 E |
CCH1 | CACNA1F | 2 | Cyt | 1-0-9 | A | 0.2 | −4.5 | 0.5 | 5.5 | [274] | calcium voltage-gated channel subunit alpha1 F |
CCH1 | NALCN | 2 | Cyt | 1-0-9 | H | 0.2 | −4.5 | 0.5 | 5.5 | sodium leak channel, non-selective | |
FAT1 | SLC27A2 | 2 | Cyt | 1-0-9 | L | 0.7 | −8.5 | −0.9 | 8.9 | [275] | solute carrier family 27 member 2 |
FAT1 | SLC27A3 | 2 | Cyt | 1-0-9 | L | 0.7 | −8.5 | −0.9 | 8.9 | [276] | solute carrier family 27 member 3 |
FOL2 | GCH1 | 1 | Cyt | 1-0-9 | L | −0.9 | −9.4 | 0.7 | 7.1 | [277] | GTP cyclohydrolase 1 |
HSL1 | BRSK1 | 3 | Cyt | 1-0-9 | A, L | 0.9 | −10.4 | 0.1 | 11.6 | [270,271] | BR serine/threonine kinase 1 |
HSL1 | BRSK2 | 3 | Cyt | 1-0-9 | A, L | 0.9 | −10.4 | 0.1 | 11.6 | [272] | BR serine/threonine kinase 2 |
IZH1 | ADIPOR1 | 3 | Cyt | 1-0-9 | H | 1.1 | −5.8 | −0.4 | 7.6 | [278,279] | adiponectin receptor 1 |
IZH1 | PAQR4 | 3 | Cyt | 1-0-9 | A, L | 1.1 | −5.8 | −0.4 | 7.6 | progestin and adipoQ receptor family member 4 | |
NAP1 | NAP1L3 | 2 | Cyt | 1-0-9 | A, L | 1.0 | −4.7 | −1.5 | 5.6 | [280] | nucleosome assembly protein 1 like 3 |
NAP1 | NAP1L4 | 2 | Cyt | 1-0-9 | L | 1.0 | −4.7 | −1.5 | 5.6 | nucleosome assembly protein 1 like 4 | |
PTM1 | TMEM87B | 3 | Cyt | 1-0-9 | A, H | −0.7 | −3.8 | −0.2 | 5.7 | [281] | transmembrane protein 87B |
6.2. Human Genes that have Deletion Enhancing Yeast Homologs and Confer Cytarabine UES
- (1)
- Ptm1, which is a protein of unknown function that copurifies with late Golgi vesicles containing the v-SNARE, Tlg2p, but interestingly, its human homologs, TMEM87A and TMEM87B, were UES for cytarabine and identified in a study focused on cytarabine efficacy in acute myelogenous leukemia [281].
- (2)
- NAP1/NAP1L3/NAP1L4, which is a nucleosome assembly protein involved in nuclear transport and exchange of histones H2A and H2B and also interacts with Clb2, is phosphorylated by CK2, and has protein abundance that increases in response to DNA replication stress [155]. NAP1L3 is overexpressed in breast cancer [280].
- (3)
- CCH1, which is a voltage-gated high-affinity calcium channel with several homologs that were UES, including: CACNA1A, underexpressed in breast, colorectal, esophageal, gastric, and brain cancers; CACNA1B, underexpressed in breast and brain cancers; CACNA1C, underexpressed in brain, bladder, lung, lymphoma, prostate, and renal cancers; CACNA1E, underexpressed in breast, brain, gastric, leukemia, lung, and prostate cancers; and CACNA1F, underexpressed in lymphoma [274].
- (4)
- (5)
- (6)
- FOL2/GCH1, a GTP-cyclohydrolase that catalyzes the first step in folic acid biosynthesis. Downregulation of GCH1 occurs in esophageal squamous cell carcinoma [277].
7. Discussion
8. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
List of Abbreviations and Glossary of Terms
References
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GO Term | Drug | INT | O | Cluster | Genes in Term | p-Value | Genes | Fig. | GTA Gem L | GTA Cyt L |
---|---|---|---|---|---|---|---|---|---|---|
Ubp3-Bre5 deubiquitination complex | Both | Enh | C | 2-0.2-0 | 2/2 | 2.57 × 10−5 | UBP3:BRE5 | Figure 5D | 19.8 | 14.32 |
positive regulation of DNA-dependent DNA replication initiation | Both | Enh | P | 1-0-2 | 3/4 | 2.09 × 10−4 | RFM1:FKH2:SUM1 | Figure 5B | 15.7 | 4.9 |
Mre11 complex | Both | Enh | C | 2-0.14-1 | 2/3 | 5.66 × 10−4 | RAD50:XRS2 | Figure 5B | 13.7 | 26.6 |
HOPS complex | Both | Enh | C | 2-0.14-1 | 2/7 | 3.94 × 10−3 | PEP3:VPS33 | Figure 5D | 12.0 | 4.8 |
CORVET complex | Both | Enh | C | 2-0.14-1 | 2/7 | 3.94 × 10−3 | PEP3:VPS33 | Figure 5D | 10.4 | 4.3 |
RecQ helicase-Topo III complex | Both | Enh | C | 1-0-14 | 2/3 | 3.31 × 10−3 | SGS1:RMI1 | Figure 5B | 7.5 | 14.6 |
GET complex | Both | Enh | C | 2-0.14-0 | 2/3 | 4.68 × 10−4 | GET1:GET2 | Figure 5D | 3.3 | 18.6 |
DNA integrity checkpoint | Both | Enh | P | 1-0-14 | 4/40 | 3.85 × 10−3 | DUN1:RAD17:RAD24:SGS1 | Figure 5A | 4.8 | 4.8 |
α-glucoside transmembrane transporter activity | Cyt | Enh | F | 2-0.17-3 | 2/2 | 5.98 × 10−3 | MAL31:MAL11 | Figure 7A | −0.7 | 2.2 |
intralumenal vesicle formation | Gem | Enh | P | 1-0-10 | 3/7 | 2.90 × 10−3 | DOA4:VPS24:BRO1 | Figure 6A | 9.0 | 1.6 |
HDA1 complex | Gem | Enh | C | 1-0-0 | 2/3 | 7.08 × 10−2 | HDA1:HDA3 | Figure 6B | 4.8 | 0.3 |
Swr1 complex | Gem | Enh | C | 1-0-11 | 3/12 | 3.46 × 10−2 | SWC3:VPS71:SWR1 | Figure 6B | 2.9 | −1.6 |
peptidyl-tyrosine dephosphorylation | Gem | Enh | P | 1-0-0 | 5/20 | 2.18 × 10−3 | OCA2:SIW14:OCA1:OCA4:OCA6 | Figure 6C | 1.5 | 0.5 |
Set1C/COMPASS complex | Gem | Enh | C | 1-0-0 | 3/6 | 5.74 × 10−3 | SDC1:SWD3:BRE2 | Figure 6B | 1.0 | 0.6 |
phospholipid-translocating ATPase activity | Gem | Sup | F | 1-0-8 | 3/7 | 9.70 × 10−3 | DRS2:LEM3:DNF2 | Figure 6D | −1.6 | −0.9 |
Term | Drug | INT_Type | Ont | Cluster | p-Value | Genes | Fig. | Gem GTA_K | Gem GTA_L | Cyt GTA_K | Cyt GTA_L |
---|---|---|---|---|---|---|---|---|---|---|---|
checkpoint clamp complex | Both | Enh L/K | C | NA | NA | RAD17 | MEC3 | Figure 5B | −7.3 | 13.8 | −23.5 | 15.4 |
HOPS complex | Both | Enh L/K | C | 2-0.14-1 | 3.94 × 10−3 | VPS16 | VPS8 | PEP3 | VPS41 | VPS33 | PEP5 | Figure 5D | −6.3 | 12.0 | −11.4 | 4.8 |
Mre11 complex | Both | Enh L/K | C | 2-0.14-1 | 5.66 × 10−4 | MRE11 | RAD50 | XRS2 | Figure 5B | −8.8 | 13.7 | −39.3 | 26.6 |
RecQ helicase-Topo III complex | Both | Enh L/K | C | 1-0-14 | 3.31 × 10−3 | RMI1 | SGS1 | TOP3 | Figure 5B | −7.7 | 7.5 | −24.7 | 14.6 |
Ubp3-Bre5 deubiquitination complex | Both | Enh L/K | C | 2-0.2-0 | 2.57 × 10−5 | UBP3 | BRE5 | Figure 5D | −9.2 | 19.8 | −16.9 | 14.3 |
vesicle fusion with vacuole | Both | Enh L/K | P | NA | NA | VAM3 | VPS33 | Figure 5D | −7.4 | 13.3 | −11.4 | 7.1 |
Sec61 translocon complex | Cyt | Enh K | C | NA | NA | SEC61 | SBH2 | Figure 7A | −0.4 | 1.1 | −5.1 | 1.9 |
HIR complex | Cyt | Enh L | C | NA | NA | HIR1 | HIR2 | HPC2 | HIR3 | Figure 7A | −1.0 | 1.0 | −0.6 | 2.5 |
sphinganine kinase activity | Cyt | Enh L | F | NA | NA | LCB4 | LCB5 | Figure 7A | −0.1 | 0.3 | −1.2 | 3.9 |
protein localization to septin ring | Cyt | Enh L/K | P | NA | NA | ELM1 | HSL1 | Figure 7A | −1.3 | 2.5 | −17.8 | 21.9 |
autophagosome maturation | Gem | Enh K | P | NA | NA | VAM3 | CCZ1 | Figure 6A | −5.6 | 7.7 | −1.6 | 2.5 |
Elongator holoenzyme complex | Gem | Enh K | C | NA | NA | TUP1 | ELP4 | ELP2 | IKI3 | IKI1 | ELP3 | ELP6 | Figure S4C | −3.6 | 3.4 | −2.6 | 2.5 |
ESCRT I complex | Gem | Enh K | C | NA | NA | STP22 | VPS28 | SRN2 | MVB12 | Figure 5D | −6.9 | 9.1 | −0.8 | 2.5 |
negative regulation of macroautophagy | Gem | Enh K | P | NA | NA | PHO85 | PHO80 | KSP1 | PCL5 | SIC1 | Figure 6A | −5.8 | 9.4 | −4.1 | 1.8 |
protein urmylation | Gem | Enh K | P | NA | NA | ELP2 | UBA4 | NCS2 | URM1 | URE2 | ELP6 | Figure S4C | −3.7 | 1.5 | 1.0 | 1.2 |
CORVET complex | Gem | Enh L/K | C | 2-0.14-1 | 3.94 × 10−3 | VPS16 | VPS8 | PEP3 | VPS41 | VPS33 | VPS3 | PEP5 | Figure 5D | −6.6 | 10.4 | −10.4 | 4.3 |
ESCRT-0 complex | Gem | Enh L/K | C | NA | NA | VPS27 | HSE1 | Figure 5D | −5.7 | 10.4 | −3.9 | 2.6 |
HDA1 complex | Gem | Enh L/K | C | 1-0-0 | 7.08 × 10−2 | HDA3 | HDA1 | HDA2 | Figure 6B | −4.8 | 4.8 | −0.6 | 0.3 |
GATOR (Iml1) complex | Gem | Enh L/K | C | NA | NA | NPR2 | NPR3 | Figure 6A | −4.4 | 6.4 | 1.0 | 2.2 |
intralumenal vesicle formation | Gem | Enh L/K | P | 1-0-10 | 2.90 × 10−3 | VPS20 | VPS24 | BRO1 | DOA4 | VPS4 | SNF7 | Figure 6A | −5.7 | 9.0 | −1.8 | 1.6 |
positive regulation of DNA-dependent DNA replication initiation | Gem | Enh L/K | P | 1-0-2 | 2.09 × 10−4 | SUM1 | FKH2 | RFM1 | FKH1 | Figure 5B | −8.1 | 15.7 | −2.4 | 4.9 |
RAVE complex | Gem | Enh L/K | C | NA | NA | RAV1 | RAV2 | Figure 6A | −4.2 | 3.5 | 0.6 | −0.2 |
GARP complex | Gem | Sup L | C | NA | NA | VPS51 | VPS53 | VPS54 | VPS52 | Figure 6D | 1.7 | −3.4 | 1.5 | −1.0 |
Lem3p-Dnf1p complex | Gem | Sup L | C | NA | NA | DNF1 | LEM3 | Figure 6D | 1.6 | −3.4 | −0.1 | 0.2 |
phosphatidylserine biosynthetic process | Gem | Sup L | C | NA | NA | DEP1 | CHO1 | UME6 | Figure 6D | 2.6 | −3.7 | 0.8 | −0.3 |
Gene (Yeast/Human) | Process/Complex | Description (Human) | Ref | Nucleoside Analog Relevance |
---|---|---|---|---|
RAD24/RAD17 | DNA damage checkpoint | RAD17 checkpoint clamp loader component | [79] | Depletion of RAD17 sensitizes pancreatic cancer cells to gemcitabine |
RAD50/RAD50 | Mre11 complex | RAD50 double strand break repair protein | [127] | Depletion of human Rad50 sensitizes Ataxia-telangiectasia (AT) fibroblasts to gemcitabine |
HDA1/HDAC6 | Hda1 complex; histone deacetylation | histone deacetylase 6 | [160,165] | HDAC inhibitors enhance sensitivity to gemcitabine in pancreatic cancer cells and are associated with reduction of HDAC6; HDAC6 inhibition induces apoptosis in cytarabine treated AML cells |
RAD54/ATRX | Chromatin remodeling | ATRX, chromatin remodeler | [168] | Glioma patients with IDH1 mutations and loss of ATRX had improved response to gemcitabine plus radiation therapy |
KEX2/PCSK7 | serine-type endopeptidase activity | proprotein convertase subtilisin/kexin type 7 | [179] | Overexpressed in gemcitabine resistant pancreatic cancer cell lines |
YNK1/NME5 | Nucleoside diphosphate phosphorylation | NME/NM23 family member 5 | [182] | Depletion of NME5 sensitizes gemcitabine-resistant cancer cell lines to gemcitabine |
VPS30/BECN1 | Autophagy | beclin 1 | [170] | Depletion of BECN1 sensitizes pancreatic cancer stem cells to gemcitabine |
LCB4/5/CERKL | sphinganine kinase activity | ceramide kinase like | [138,264] | CERKL stabilizes SIRT1, SIRT1 chemical inhibition sensitizes acute myeloid leukemia cells to cytarabine |
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Santos, S.M.; Icyuz, M.; Pound, I.; William, D.; Guo, J.; McKinney, B.A.; Niederweis, M.; Rodgers, J.; Hartman, J.L., IV. A Humanized Yeast Phenomic Model of Deoxycytidine Kinase to Predict Genetic Buffering of Nucleoside Analog Cytotoxicity. Genes 2019, 10, 770. https://doi.org/10.3390/genes10100770
Santos SM, Icyuz M, Pound I, William D, Guo J, McKinney BA, Niederweis M, Rodgers J, Hartman JL IV. A Humanized Yeast Phenomic Model of Deoxycytidine Kinase to Predict Genetic Buffering of Nucleoside Analog Cytotoxicity. Genes. 2019; 10(10):770. https://doi.org/10.3390/genes10100770
Chicago/Turabian StyleSantos, Sean M., Mert Icyuz, Ilya Pound, Doreen William, Jingyu Guo, Brett A. McKinney, Michael Niederweis, John Rodgers, and John L. Hartman, IV. 2019. "A Humanized Yeast Phenomic Model of Deoxycytidine Kinase to Predict Genetic Buffering of Nucleoside Analog Cytotoxicity" Genes 10, no. 10: 770. https://doi.org/10.3390/genes10100770