The Kub5-Hera/RPRD1B interactome: a novel role in preserving genetic stability by regulating DNA mismatch repair

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dc.contributor.authorPatidar, Praveen L.en
dc.contributor.authorMotea, Edward A.en
dc.contributor.authorFattah, Farjana J.en
dc.contributor.authorZhou, Yunyunen
dc.contributor.authorMorales, Julio C.en
dc.contributor.authorXie, Yangen
dc.contributor.authorGarner, Harold R.en
dc.contributor.authorBoothman, David A.en
dc.date.accessioned2019-04-11T18:07:53Zen
dc.date.available2019-04-11T18:07:53Zen
dc.date.issued2016-02-29en
dc.description.abstractKu70-binding protein 5 (Kub5)-Hera (K-H)/RPRD1B maintains genetic integrity by concomitantly minimizing persistent R-loops and promoting repair of DNA double strand breaks (DSBs). We used tandem affinity purification-mass spectrometry, coimmunoprecipitation and gel-filtration chromatography to define higher-order protein complexes containing K-H scaffolding protein to gain insight into its cellular functions. We confirmed known protein partners (Ku70, RNA Pol II, p15RS) and discovered several novel associated proteins that function in RNA metabolism (Topoisomerase 1 and RNA helicases), DNA repair/replication processes (PARP1, MSH2, Ku, DNA-PKcs, MCM proteins, PCNA and DNA Pol delta) and in protein metabolic processes, including translation. Notably, this approach directed us to investigate an unpredicted involvement of K-H in DNA mismatch repair (MMR) where K-H depletion led to concomitant MMR deficiency and compromised global microsatellite stability. Mechanistically, MMR deficiency in K-H-depleted cells was a consequence of reduced stability of the core MMR proteins (MLH1 and PMS2) caused by elevated basal caspase-dependent proteolysis. Pan-caspase inhibitor treatment restored MMR protein loss. These findings represent a novel mechanism to acquire MMR deficiency/microsatellite alterations. A significant proportion of colon, endometrial and ovarian cancers exhibit k-h expression/copy number loss and may have severe mutator phenotypes with enhanced malignancies that are currently overlooked based on sporadic MSI+ screening.en
dc.description.notesNational Institutes of Health/National Cancer Institute (NCI/NIH) [R01 CA139217 to D.A.B.]; NCI/NIH [5P30CA142543 to the UT Southwestern Proteomics Core]; NCI/NIH [UT Southwestern CCSG grant 5P30CA142543]; a minority supplement [R01 CA139217-05S1 to E.A.M.]; Cancer Biology Training Grant [T32CA124334-06 (PI: Dr Jerry Shay) to E.A.M.]; Simmons Comprehensive Cancer Center; Cancer Prevention and Research Institute of Texas [CPRIT, RP1206130 to Dr Hamid Mirzaei and UT Southwestern Proteomics Core, in part]. Funding for open access charge: National Institutes of Health/National Cancer Institute (NIH/NCI) [R01 CA139217].en
dc.description.sponsorshipNational Institutes of Health/National Cancer Institute (NCI/NIH) [R01 CA139217]; NCI/NIH [5P30CA142543]; NCI/NIH [UT Southwestern CCSG grant] [5P30CA142543]; Cancer Biology Training Grant [T32CA124334- 06]; Simmons Comprehensive Cancer Center; Cancer Prevention and Research Institute of Texas [CPRIT] [RP1206130]; [R01 CA139217-05S1]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1093/nar/gkv1492en
dc.identifier.eissn1362-4962en
dc.identifier.issn0305-1048en
dc.identifier.issue4en
dc.identifier.pmid26819409en
dc.identifier.urihttp://hdl.handle.net/10919/88891en
dc.identifier.volume44en
dc.language.isoen_USen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectnonpolyposis colorectal-canceren
dc.subjectcell-cycle checkpointen
dc.subjectstrand-break repairen
dc.subjectrna-polymerase-iien
dc.subjectproteomics facilities pipelineen
dc.subjectcolon-canceren
dc.subjecttranscription terminationen
dc.subjectsaccharomyces-cerevisiaeen
dc.subjectmammalian chromosomesen
dc.subjectassociating proteinsen
dc.titleThe Kub5-Hera/RPRD1B interactome: a novel role in preserving genetic stability by regulating DNA mismatch repairen
dc.title.serialNucleic Acids Researchen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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