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Article: MAD2 Interacts with DNA Repair Proteins and Negatively Regulates DNA Damage Repair

TitleMAD2 Interacts with DNA Repair Proteins and Negatively Regulates DNA Damage Repair
Authors
Issue Date2008
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmb
Citation
Journal Of Molecular Biology, 2008, v. 381 n. 1, p. 24-34 How to Cite?
AbstractMAD2 (mitotic arrest deficient 2) is a key regulator of mitosis. Recently, it had been suggested that MAD2-induced mitotic arrest mediates DNA damage response and that upregulation of MAD2 confers sensitivity to DNA-damaging anticancer drug-induced apoptosis. In this study, we report a potential novel role of MAD2 in mediating DNA nucleotide excision repair through physical interactions with two DNA repair proteins, XPD (xeroderma pigmentosum complementation group D) and ERCC1. First, overexpression of MAD2 resulted in decreased nuclear accumulation of XPD, a crucial step in the initiation of DNA repair. Second, immunoprecipitation experiments showed that MAD2 was able to bind to XPD, which led to competitive suppression of binding activity between XPD and XPA, resulting in the prevention of physical interactions between DNA repair proteins. Third, unlike its role in mitosis, the N-terminus domain seemed to be more important in the binding activity between MAD2 and XPD. Fourth, phosphorylation of H2AX, a process that is important for recruitment of DNA repair factors to DNA double-strand breaks, was suppressed in MAD2-overexpressing cells in response to DNA damage. These results suggest a negative role of MAD2 in DNA damage response, which may be accounted for its previously reported role in promoting sensitivity to DNA-damaging agents in cancer cells. However, the interaction between MAD2 and ERCC1 did not show any effect on the binding activity between ERCC1 and XPA in the presence or absence of DNA damage. Our results suggest a novel function of MAD2 by interfering with DNA repair proteins. © 2008 Elsevier Ltd. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/58181
ISSN
2015 Impact Factor: 4.517
2015 SCImago Journal Rankings: 3.002
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorFung, MKLen_HK
dc.contributor.authorHan, HYen_HK
dc.contributor.authorLeung, SCLen_HK
dc.contributor.authorCheung, HWen_HK
dc.contributor.authorCheung, ALMen_HK
dc.contributor.authorWong, YCen_HK
dc.contributor.authorLing, MTen_HK
dc.contributor.authorWang, Xen_HK
dc.date.accessioned2010-05-31T03:25:19Z-
dc.date.available2010-05-31T03:25:19Z-
dc.date.issued2008en_HK
dc.identifier.citationJournal Of Molecular Biology, 2008, v. 381 n. 1, p. 24-34en_HK
dc.identifier.issn0022-2836en_HK
dc.identifier.urihttp://hdl.handle.net/10722/58181-
dc.description.abstractMAD2 (mitotic arrest deficient 2) is a key regulator of mitosis. Recently, it had been suggested that MAD2-induced mitotic arrest mediates DNA damage response and that upregulation of MAD2 confers sensitivity to DNA-damaging anticancer drug-induced apoptosis. In this study, we report a potential novel role of MAD2 in mediating DNA nucleotide excision repair through physical interactions with two DNA repair proteins, XPD (xeroderma pigmentosum complementation group D) and ERCC1. First, overexpression of MAD2 resulted in decreased nuclear accumulation of XPD, a crucial step in the initiation of DNA repair. Second, immunoprecipitation experiments showed that MAD2 was able to bind to XPD, which led to competitive suppression of binding activity between XPD and XPA, resulting in the prevention of physical interactions between DNA repair proteins. Third, unlike its role in mitosis, the N-terminus domain seemed to be more important in the binding activity between MAD2 and XPD. Fourth, phosphorylation of H2AX, a process that is important for recruitment of DNA repair factors to DNA double-strand breaks, was suppressed in MAD2-overexpressing cells in response to DNA damage. These results suggest a negative role of MAD2 in DNA damage response, which may be accounted for its previously reported role in promoting sensitivity to DNA-damaging agents in cancer cells. However, the interaction between MAD2 and ERCC1 did not show any effect on the binding activity between ERCC1 and XPA in the presence or absence of DNA damage. Our results suggest a novel function of MAD2 by interfering with DNA repair proteins. © 2008 Elsevier Ltd. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmben_HK
dc.relation.ispartofJournal of Molecular Biologyen_HK
dc.subject.meshCalcium-Binding Proteins - genetics - metabolismen_HK
dc.subject.meshCell Cycle Proteins - genetics - metabolismen_HK
dc.subject.meshCell Lineen_HK
dc.subject.meshCisplatin - pharmacologyen_HK
dc.subject.meshDNA - genetics - metabolismen_HK
dc.subject.meshDNA Damage - geneticsen_HK
dc.subject.meshDNA Repair - geneticsen_HK
dc.subject.meshDNA-Binding Proteins - metabolismen_HK
dc.subject.meshGene Expression Regulation - drug effectsen_HK
dc.subject.meshHistones - metabolismen_HK
dc.subject.meshHumansen_HK
dc.subject.meshProtein Bindingen_HK
dc.subject.meshRad51 Recombinase - metabolismen_HK
dc.subject.meshRepressor Proteins - genetics - metabolismen_HK
dc.subject.meshXeroderma Pigmentosum Group D Protein - metabolismen_HK
dc.titleMAD2 Interacts with DNA Repair Proteins and Negatively Regulates DNA Damage Repairen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0022-2836&volume=381&spage=24&epage=34&date=2008&atitle=MAD2+Interacts+with+DNA+Repair+Proteins+and+Negatively+Regulates+DNA+Damage+Repair.en_HK
dc.identifier.emailCheung, ALM:lmcheung@hkucc.hku.hken_HK
dc.identifier.emailWong, YC:ycwong@hkucc.hku.hken_HK
dc.identifier.emailLing, MT:patling@hkucc.hku.hken_HK
dc.identifier.authorityCheung, ALM=rp00332en_HK
dc.identifier.authorityWong, YC=rp00316en_HK
dc.identifier.authorityLing, MT=rp00449en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.jmb.2008.05.080en_HK
dc.identifier.pmid18597777-
dc.identifier.scopuseid_2-s2.0-46649103822en_HK
dc.identifier.hkuros147349en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-46649103822&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume381en_HK
dc.identifier.issue1en_HK
dc.identifier.spage24en_HK
dc.identifier.epage34en_HK
dc.identifier.isiWOS:000258197500003-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridFung, MKL=8718040400en_HK
dc.identifier.scopusauthoridHan, HY=24477301600en_HK
dc.identifier.scopusauthoridLeung, SCL=36894169100en_HK
dc.identifier.scopusauthoridCheung, HW=7201839381en_HK
dc.identifier.scopusauthoridCheung, ALM=7401806497en_HK
dc.identifier.scopusauthoridWong, YC=7403041798en_HK
dc.identifier.scopusauthoridLing, MT=7102229780en_HK
dc.identifier.scopusauthoridWang, X=7501854829en_HK

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