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PMID:20304803

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Citation

Kang, TH, Lindsey-Boltz, LA, Reardon, JT and Sancar, A (2010) Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proc. Natl. Acad. Sci. U.S.A. 107:4890-5

Abstract

Cisplatin is one of the most commonly used anticancer drugs. It kills cancer cells by damaging their DNA, and hence cellular DNA repair capacity is an important determinant of its efficacy. Here, we investigated the repair of cisplatin-induced DNA damage in mouse liver and testis tissue extracts prepared at regular intervals over the course of a day. We find that the XPA protein, which plays an essential role in repair of cisplatin damage by nucleotide excision repair, exhibits circadian oscillation in the liver but not in testis. Consequently, removal of cisplatin adducts in liver extracts, but not in testis extracts, exhibits a circadian pattern with zenith at approximately 5 pm and nadir at approximately 5 am. Furthermore, we find that the circadian oscillation of XPA is achieved both by regulation of transcription by the core circadian clock proteins including cryptochrome and by regulation at the posttranslational level by the HERC2 ubiquitin ligase. These findings may be used as a guide for timing of cisplatin chemotherapy.

Links

PubMed PMC2841896 Online version:10.1073/pnas.0915085107

Keywords

Animals; Biological Clocks/drug effects; Cell Line; Circadian Rhythm/drug effects; Cisplatin/pharmacology; Cryptochromes/metabolism; DNA Adducts/metabolism; DNA Damage; DNA Repair/drug effects; Down-Regulation/drug effects; Guanine Nucleotide Exchange Factors/metabolism; Humans; Liver/drug effects; Liver/metabolism; Male; Mice; Protein Binding/drug effects; Protein Processing, Post-Translational/drug effects; RNA, Messenger/genetics; RNA, Messenger/metabolism; Testis/drug effects; Testis/metabolism; Time Factors; Tissue Extracts; Xeroderma Pigmentosum Group A Protein/genetics; Xeroderma Pigmentosum Group A Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HERC2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P23025

F

Seeded From UniProt

complete

HUMAN:HERC2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HERC2

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HERC2

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RFA2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P23025

F

Seeded From UniProt

complete

HUMAN:XPA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O95714

F

Seeded From UniProt

complete

HUMAN:XPA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15927

F

Seeded From UniProt

complete

HUMAN:HERC2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HERC2

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HERC2

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HERC2

involved_in

GO:0016567: protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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