title: 53BP1 alters the landscape of DNA rearrangements and suppresses AID-induced B cell lymphoma.
abstract: Deficiencies in factors that regulate the DNA damage response enhance the incidence of malignancy by destabilizing the genome. However, the precise influence of the DNA damage response on regulation of cancer-associated rearrangements is not well defined. Here we examine the genome-wide impact of tumor protein P53-binding protein 1 (53BP1) deficiency in lymphoma and translocation. While both activation-induced cytidine deaminase (AID) and 53BP1 have been associated with cancer in humans, neither AID overexpression nor loss of 53BP1 is sufficient to produce malignancy. However, the combination of 53BP1 deficiency and AID deregulation results in B cell lymphoma. Deep sequencing of the genome of 53BP1(-/-) cancer cells and translocation capture sequencing (TC-Seq) of primary 53BP1(-/-) B cells revealed that their chromosomal rearrangements differ from those found in wild-type cells in that they show increased DNA end resection. Moreover, loss of 53BP1 alters the translocatome by increasing rearrangements to intergenic regions.
authors.affiliation: Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Mila
authors.initials: M
authors.lastname: Jankovic
authors.forename: Niklas
authors.initials: N
authors.lastname: Feldhahn
authors.forename: Thiago Y
authors.initials: TY
authors.lastname: Oliveira
authors.forename: Israel T
authors.initials: IT
authors.lastname: Silva
authors.forename: Kyong-Rim
authors.initials: KR
authors.lastname: Kieffer-Kwon
authors.forename: Arito
authors.initials: A
authors.lastname: Yamane
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Resch
authors.forename: Isaac
authors.initials: I
authors.lastname: Klein
authors.forename: Davide F
authors.initials: DF
authors.lastname: Robbiani
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D033481:Chromosomes, Mammalian / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic; D015321:Gene Rearrangement; D016147:Genes, Tumor Suppressor; D055106:Genome-Wide Association Study; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase