Show simple item record

dc.contributor.authorKhair, Lyne
dc.contributor.authorGuikema, Jeroen E. J.
dc.contributor.authorLinehan, Erin K.
dc.contributor.authorUcher, Anna J.
dc.contributor.authorLeus, Niek G.J.
dc.contributor.authorOgilvie, Colin
dc.contributor.authorLou, Zhenkun
dc.contributor.authorSchrader, Carol E.
dc.contributor.authorStavnezer, Janet
dc.date2022-08-11T08:08:32.000
dc.date.accessioned2022-08-23T15:58:25Z
dc.date.available2022-08-23T15:58:25Z
dc.date.issued2014-05-15
dc.date.submitted2015-08-10
dc.identifier.citationJ Immunol. 2014 May 15;192(10):4887-96. doi: 10.4049/jimmunol.1303481. Epub 2014 Apr 11. <a href="http://dx.doi.org/10.4049/jimmunol.1303481">Link to article on publisher's site</a>
dc.identifier.issn0022-1767 (Linking)
dc.identifier.doi10.4049/jimmunol.1303481
dc.identifier.pmid24729610
dc.identifier.urihttp://hdl.handle.net/20.500.14038/30428
dc.description.abstractActivation-induced cytidine deaminase (AID) initiates Ab class-switch recombination (CSR) in activated B cells resulting in exchanging the IgH C region and improved Ab effector function. During CSR, AID instigates DNA double-strand break (DSB) formation in switch (S) regions located upstream of C region genes. DSBs are necessary for CSR, but improper regulation of DSBs can lead to chromosomal translocations that can result in B cell lymphoma. The protein kinase ataxia telangiectasia mutated (ATM) is an important proximal regulator of the DNA damage response (DDR), and translocations involving S regions are increased in its absence. ATM phosphorylates H2AX, which recruits other DNA damage response (DDR) proteins, including mediator of DNA damage checkpoint 1 (Mdc1) and p53 binding protein 1 (53BP1), to sites of DNA damage. As these DDR proteins all function to promote repair and recombination of DSBs during CSR, we examined whether mouse splenic B cells deficient in these proteins would show alterations in S region DSBs when undergoing CSR. We find that in atm(-/-) cells Smu DSBs are increased, whereas DSBs in downstream Sgamma regions are decreased. We also find that mutations in the unrearranged Sgamma3 segment are reduced in atm(-/-) cells. Our data suggest that ATM increases AID targeting and activity at downstream acceptor S regions during CSR and that in atm(-/-) cells Smu DSBs accumulate as they lack a recombination partner.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=24729610&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049217/
dc.subjectAnimals
dc.subjectAtaxia Telangiectasia Mutated Proteins
dc.subjectChromosomal Proteins, Non-Histone
dc.subjectCytidine Deaminase
dc.subjectDNA Damage
dc.subjectDNA-Binding Proteins
dc.subjectGene Rearrangement, B-Lymphocyte
dc.subjectHistones
dc.subjectIntracellular Signaling Peptides and Proteins
dc.subjectMice
dc.subjectMice, Knockout
dc.subjectPhosphorylation
dc.subjectGenetics and Genomics
dc.subjectImmunology and Infectious Disease
dc.titleATM increases activation-induced cytidine deaminase activity at downstream S regions during class-switch recombination
dc.typeJournal Article
dc.source.journaltitleJournal of immunology (Baltimore, Md. : 1950)
dc.source.volume192
dc.source.issue10
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/701
dc.identifier.contextkey7435816
html.description.abstract<p>Activation-induced cytidine deaminase (AID) initiates Ab class-switch recombination (CSR) in activated B cells resulting in exchanging the IgH C region and improved Ab effector function. During CSR, AID instigates DNA double-strand break (DSB) formation in switch (S) regions located upstream of C region genes. DSBs are necessary for CSR, but improper regulation of DSBs can lead to chromosomal translocations that can result in B cell lymphoma. The protein kinase ataxia telangiectasia mutated (ATM) is an important proximal regulator of the DNA damage response (DDR), and translocations involving S regions are increased in its absence. ATM phosphorylates H2AX, which recruits other DNA damage response (DDR) proteins, including mediator of DNA damage checkpoint 1 (Mdc1) and p53 binding protein 1 (53BP1), to sites of DNA damage. As these DDR proteins all function to promote repair and recombination of DSBs during CSR, we examined whether mouse splenic B cells deficient in these proteins would show alterations in S region DSBs when undergoing CSR. We find that in atm(-/-) cells Smu DSBs are increased, whereas DSBs in downstream Sgamma regions are decreased. We also find that mutations in the unrearranged Sgamma3 segment are reduced in atm(-/-) cells. Our data suggest that ATM increases AID targeting and activity at downstream acceptor S regions during CSR and that in atm(-/-) cells Smu DSBs accumulate as they lack a recombination partner.</p>
dc.identifier.submissionpathfaculty_pubs/701
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.source.pages4887-96


This item appears in the following Collection(s)

Show simple item record