title: tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma.
abstract: Sequencing studies from several model systems have suggested that diverse and abundant small RNAs may be derived from tRNA, but the function of these molecules remains undefined. Here, we demonstrate that one such tRNA-derived fragment, cloned from human mature B cells and designated CU1276, in fact possesses the functional characteristics of a microRNA, including a DICER1-dependent biogenesis, physical association with Argonaute proteins, and the ability to repress mRNA transcripts in a sequence-specific manner. Expression of CU1276 is abundant in normal germinal center B cells but absent in germinal center-derived lymphomas, suggesting a role in the pathogenesis of this disease. Furthermore, CU1276 represses endogenous RPA1, an essential gene involved in many aspects of DNA dynamics, and consequently, expression of this tRNA-derived microRNA in a lymphoma cell line suppresses proliferation and modulates the molecular response to DNA damage. These results establish that functionally active microRNAs can be derived from tRNA, thus defining a class of genetic entities with potentially important biological roles.
authors.affiliation: Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Maute
authors.forename: Christof
authors.initials: C
authors.lastname: Schneider
authors.forename: Pavel
authors.initials: P
authors.lastname: Sumazin
authors.forename: Antony
authors.initials: A
authors.lastname: Holmes
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.forename: Katia
authors.initials: K
authors.lastname: Basso
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
mesh_terms: D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D015536:Down-Regulation; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D012334:RNA, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D012343:RNA, Transfer / Q000235:genetics* / Q000378:metabolism*; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism
chemical_list: D060565:Argonaute Proteins; D035683:MicroRNAs; D012334:RNA, Neoplasm; C497167:RPA1 protein, human; D051716:Replication Protein A; D012343:RNA, Transfer; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases