Genetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndrome

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dc.contributor.authorDhangada Majhi, Prabin
dc.contributor.authorGriner, Nicholas B
dc.contributor.authorMayfield, Jacob A
dc.contributor.authorCompton, Shannon
dc.contributor.authorKane, Jeffrey J
dc.contributor.authorBaptiste, Trevor A
dc.contributor.authorDunphy, K.A.
dc.contributor.authorRoberts, Amy L.
dc.contributor.authorSchneider, S
dc.contributor.authorSavage, Evan M
dc.contributor.authorBlackburn, Anneke
dc.date.accessioned2023-08-20T23:45:05Z
dc.date.issued2021
dc.date.updated2022-07-24T08:19:06Z
dc.description.abstractBreast cancer is the most common tumor among women with inherited variants in the TP53 tumor suppressor, but onset varies widely suggesting interactions with genetic or environmental factors. Rodent models haploinsufficent for Trp53 also develop a wide variety of malignancies associated with Li-Fraumeni syndrome, but BALB/c mice are uniquely susceptible to mammary tumors and is genetically linked to the Suprmam1 locus on chromosome 7. To define mechanisms that interact with deficiencies in p53 to alter susceptibility to mammary tumors, we fine mapped the Suprmam1 locus in females from an N2 backcross of BALB/cMed and C57BL/6J mice. A major modifier was localized within a 10 cM interval on chromosome 7. The effect of the locus on DNA damage responses was examined in the parental strains and mice that are congenic for C57BL/6J alleles on the BALB/cMed background (SM1-Trp53(+/-)). The mammary epithelium of C57BL/6J-Trp53(+/-) females exhibited little radiation-induced apoptosis compared to BALB/cMed-Trp53(+/-) and SM1-Trp53(+/-) females indicating that the Suprmam1(B6/B6) alleles could not rescue repair of radiation-induced DNA double-strand breaks mostly relying on non-homologous end joining. In contrast, the Suprmam1(B6/B6) alleles in SM1-Trp53(+/-) mice were sufficient to confer the C57BL/6J-Trp53(+/-) phenotypes in homology-directed repair and replication fork progression. The Suprmam1(B6/B6) alleles in SM1-Trp53(+/-) mice appear to act in trans to regulate a panel of DNA repair and replication genes which lie outside the locus.en_AU
dc.description.sponsorshipResearch reported in this publication was supported, in part, by the National Institute of Environmental Health Sciences of the National Institutes of Health under award number R01CA105452 (DJJ), U01ES026140 (DJJ, SSS), the Department of Defense under contract #W81XWH-15-1-0217 (DJJ) and the Rays of Hope Center for Breast Cancer Research (DJJ), University Grants Commission (India) for Raman Fellowship for post-doctoral research (PDM) as well as by the German Research Foundation (DFG, Research Training Group 2554 to LW) and by the DFG-funded Graduate School of Molecular Medicine, Ulm University (PhD fellowship to KJM).en_AU
dc.format.mimetypeapplication/pdfen_AU
dc.identifier.issn0950-9232en_AU
dc.identifier.urihttp://hdl.handle.net/1885/296677
dc.language.isoen_AUen_AU
dc.publisherNature Publishing Groupen_AU
dc.rights© The Author(s), under exclusive licence to Springer Nature Limited 2021en_AU
dc.sourceOncogeneen_AU
dc.titleGenetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndromeen_AU
dc.typeJournal articleen_AU
local.bibliographicCitation.issue31en_AU
local.bibliographicCitation.lastpage5037en_AU
local.bibliographicCitation.startpage5026en_AU
local.contributor.affiliationDhangada Majhi, Prabin, University of Massachusetts Amhersten_AU
local.contributor.affiliationGriner, Nicholas B, University of Massachusetts Amhersten_AU
local.contributor.affiliationMayfield, Jacob A, Brigham and Women's Hospitalen_AU
local.contributor.affiliationCompton, Shannon, University of Massachusetts Amhersten_AU
local.contributor.affiliationKane, Jeffrey J, University of Massachusetts Amhersten_AU
local.contributor.affiliationBaptiste, Trevor A, University of Massachusetts Amhersten_AU
local.contributor.affiliationDunphy, K.A., University of Massachusettsen_AU
local.contributor.affiliationRoberts, Amy L., University of Massachusettsen_AU
local.contributor.affiliationSchneider, S, University of Massachusettsen_AU
local.contributor.affiliationSavage, Evan M, Genome Explorationsen_AU
local.contributor.affiliationBlackburn, Anneke, College of Health and Medicine, ANUen_AU
local.contributor.authoremailu4048450@anu.edu.auen_AU
local.contributor.authoruidBlackburn, Anneke, u4048450en_AU
local.description.embargo2099-12-31
local.description.notesImported from ARIESen_AU
local.identifier.absfor321101 - Cancer cell biologyen_AU
local.identifier.absfor321103 - Cancer geneticsen_AU
local.identifier.ariespublicationa383154xPUB20768en_AU
local.identifier.citationvolume40en_AU
local.identifier.doi10.1038/s41388-021-01892-5en_AU
local.identifier.thomsonIDWOS:000667587200001
local.identifier.uidSubmittedBya383154en_AU
local.publisher.urlhttps://www.nature.com/en_AU
local.type.statusPublished Versionen_AU

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