title: Functional and physical interactions between ERCC1 and MSH2 complexes for resistance to cis-diamminedichloroplatinum(II) in mammalian cells.
abstract: Bulky DNA lesions are mainly repaired by nucleotide excision repair (NER), in which the interaction of ERCC1 with XPA protein recruits the ERCC1-XPF complex, which acts as a structure-specific endonuclease in the repair process. However, additional functions besides NER have been suggested for the ERCC1-XPF complex, because ERCC1- or XPF-deficient rodent cells are significantly more sensitive to DNA interstrand cross-linking (ICL) agents such as cis-diamminedichloroplatinum(II) (CDDP) than any other NER-deficient cells and because ERCC1-deficient mice suffer a more severe phenotype than XPA-deficient mice. By using RNA interference we show here that suppression of ERCC1 expression increases the sensitivity of xeroderma pigmentosum group A (XPA)-deficient human cells to CDDP but not to UV. This increased sensitivity to CDDP is observed in mouse cells defective in Xpa as well but not in cells defective both in Xpa and the mismatch repair gene Msh2. These data suggest that ERCC1 and MSH2 are involved co-operatively in CDDP resistance in mammalian cells. As a possible molecular basis, we show further a physical interaction between endogenous ERCC1 and MSH2 complexes in HeLa cell extracts. Using tagged ERCC1 in COS7 cells, the minimum region in ERCC1 necessary for the immuno-precipitation of MSH2 is turned out to be the carboxyl-terminal domain between the 184th and 260th amino acid, which is partly overlapping with the XPF-binding domain of ERCC1. This interaction may be important in additional functions of ERCC1-XPF including the repair of CDDP-induced DNA damage.
authors.affiliation: Department of Molecular Genetics, Aging and Cancer, Tohoku University, 980-8575 Sendai, Japan.
authors.forename: Li
authors.initials: L
authors.lastname: Lan
authors.forename: Tsuyuko
authors.initials: T
authors.lastname: Hayashi
authors.forename: Rokshana M
authors.initials: RM
authors.lastname: Rabeya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakajima
authors.forename: Shin ichiro
authors.initials: Si
authors.lastname: Kanno
authors.forename: Masashi
authors.initials: M
authors.lastname: Takao
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yoshino
authors.forename: Minoru
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Hein te
authors.initials: Ht
authors.lastname: Riele
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Kiyoji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Akira
authors.initials: A
authors.lastname: Yasui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019556:COS Cells / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002522:Chlorocebus aethiops; D002945:Cisplatin / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004351:Drug Resistance; D004720:Endonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D051718:MutS Homolog 2 Protein; D011233:Precipitin Tests; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum; D051760:Xeroderma Pigmentosum Group A Protein
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C095888:xeroderma pigmentosum group F protein; C071447:ERCC1 protein, human; D004720:Endonucleases; C499360:Ercc1 protein, mouse; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D002945:Cisplatin