Table 5 Literature supporting the yeast phenomic doxorubicin model

MUS81/MUS81

Topological change

MUS81

MUS81 structure-specific endonuclease subunit

[103, 181, 182]

Knockdown (shRNA) increases cisplatin and epirubicin (doxorubicin analog)-induced apoptosis of HCC cells.

SOD1/SOD1/CCS

Oxidative stress: complexes III and IV; protein import into mito matrix

SOD1; CCS

Superoxide dismutase

[8, 11, 72,73,74]

Doxorubicin causes depletion of cardiolipin and cytochrome c in cardiomyocytes, which reduces workload capacity and accelerates aging; TIM/TOM deficiency induces oxidative stress, oxidative stress enhances doxorubicin toxicity.

CDC8/DTYMK; CDC21/TYMS

dTTP biosynthetic process

NA

Thymidylate kinase; thymidylate synthetase

[127]

shRNA silencing of DTYMK enhances doxorubicin in cancer cell lines.

HDA1/HDAC6

Histone deacetylation

HDAC6

Histone deacetylase 6

[235, 236]

shRNA inhibition of HDAC6 enhances doxorubicin treatment; HDAC6 inhibition reduces cardiomyocyte toxicity.

VPS53/VPS53

Sphingolipid homeostasis

VPS53

GARP complex subunit

[204]

Transfection with VPS53 transcript induces apoptosis and sensitizes cervical cancer cells to doxorubicin.

ELO2/3/ELOVL6

Fatty acid elongase activity; ceramide/phytosphingosine

ELOVL6

ELOVL fatty acid elongase 6; doxorubicin induces ceramide overproduction contributing to doxorubicin induced apoptosis

[12, 13, 150,151,152,153,154,155,156]

Loss of genes involved in sphingolipid/ceramide metabolism suppress doxorubicin cytotoxicity in our experiment; treatment with by N,N-dimethyl phytosphingosine sensitizes leukemia cells to doxorubicin.

POB3/SSRP1

FACT complex

SSRP1

Structure-specific recognition protein 1

[20]

FACT complex binds and “traps” disassembled chromatin in response to doxorubicin induced nucleosome disassembly, which induces chromatin damage.

ARP2/ACTR2

Actin cortical patch localization; APR2/3 complex

ACTR2

ARP2 actin-related protein 2 homolog

[158,159,160,161,162, 188]

ROCK1 deletion enhances doxorubicin resistance in fibroblasts by altering the actin cytoskeleton and protecting from apoptosis.