Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations

Chengming Zhu; Kevin D Mills; David O Ferguson; Charles Lee; John Manis; James Fleming; Yijie Gao; Cynthia C Morton; Frederick W Alt

Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations

Chengming Zhu, Kevin D Mills, David O Ferguson, Charles Lee, John Manis, James Fleming, Yijie Gao, Cynthia C Morton, Frederick W Alt

Division of Evolution, Infection and Genomics

Research output: Contribution to journal › Article › peer-review

Abstract

Amplification of large genomic regions associated with complex translocations (complicons) is a basis for tumor progression and drug resistance. We show that pro-B lymphomas in mice deficient for both p53 and nonhomologous end-joining (NHEJ) contain complicons that coamplify c-myc (chromosome 15) and IgH (chromosome 12) sequences. While all carry a translocated (12;15) chromosome, coamplified sequences are located within a separate complicon that often involves a third chromosome. Complicon formation is initiated by recombination of RAG1/2-catalyzed IgH locus double-strand breaks with sequences downstream of c-myc, generating a dicentric (15;12) chromosome as an amplification intermediate. This recombination event employs a microhomology-based end-joining repair pathway, as opposed to classic NHEJ or homologous recombination. These findings suggest a general model for oncogenic complicon formation.

Original language	English
Pages (from-to)	811-21
Number of pages	11
Journal	Cell
Volume	109
Issue number	7
Publication status	Published - 28 Jun 2002

Keywords

Animals
Base Sequence
Chromosomes
DNA Damage
DNA Repair
Gene Amplification
Gene Expression Regulation, Neoplastic
Genes, RAG-1
Genes, myc
In Situ Hybridization, Fluorescence
Lymphoma, B-Cell
Mice
Molecular Sequence Data
RNA, Messenger
Recombination, Genetic
Translocation, Genetic
Tumor Suppressor Protein p53
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

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title = "Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations",

abstract = "Amplification of large genomic regions associated with complex translocations (complicons) is a basis for tumor progression and drug resistance. We show that pro-B lymphomas in mice deficient for both p53 and nonhomologous end-joining (NHEJ) contain complicons that coamplify c-myc (chromosome 15) and IgH (chromosome 12) sequences. While all carry a translocated (12;15) chromosome, coamplified sequences are located within a separate complicon that often involves a third chromosome. Complicon formation is initiated by recombination of RAG1/2-catalyzed IgH locus double-strand breaks with sequences downstream of c-myc, generating a dicentric (15;12) chromosome as an amplification intermediate. This recombination event employs a microhomology-based end-joining repair pathway, as opposed to classic NHEJ or homologous recombination. These findings suggest a general model for oncogenic complicon formation.",

keywords = "Animals, Base Sequence, Chromosomes, DNA Damage, DNA Repair, Gene Amplification, Gene Expression Regulation, Neoplastic, Genes, RAG-1, Genes, myc, In Situ Hybridization, Fluorescence, Lymphoma, B-Cell, Mice, Molecular Sequence Data, RNA, Messenger, Recombination, Genetic, Translocation, Genetic, Tumor Suppressor Protein p53, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.",

author = "Chengming Zhu and Mills, \{Kevin D\} and Ferguson, \{David O\} and Charles Lee and John Manis and James Fleming and Yijie Gao and Morton, \{Cynthia C\} and Alt, \{Frederick W\}",

year = "2002",

month = jun,

day = "28",

language = "English",

volume = "109",

pages = "811--21",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier BV",

number = "7",

}

TY - JOUR

T1 - Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations

AU - Zhu, Chengming

AU - Mills, Kevin D

AU - Ferguson, David O

AU - Lee, Charles

AU - Manis, John

AU - Fleming, James

AU - Gao, Yijie

AU - Morton, Cynthia C

AU - Alt, Frederick W

PY - 2002/6/28

Y1 - 2002/6/28

N2 - Amplification of large genomic regions associated with complex translocations (complicons) is a basis for tumor progression and drug resistance. We show that pro-B lymphomas in mice deficient for both p53 and nonhomologous end-joining (NHEJ) contain complicons that coamplify c-myc (chromosome 15) and IgH (chromosome 12) sequences. While all carry a translocated (12;15) chromosome, coamplified sequences are located within a separate complicon that often involves a third chromosome. Complicon formation is initiated by recombination of RAG1/2-catalyzed IgH locus double-strand breaks with sequences downstream of c-myc, generating a dicentric (15;12) chromosome as an amplification intermediate. This recombination event employs a microhomology-based end-joining repair pathway, as opposed to classic NHEJ or homologous recombination. These findings suggest a general model for oncogenic complicon formation.

AB - Amplification of large genomic regions associated with complex translocations (complicons) is a basis for tumor progression and drug resistance. We show that pro-B lymphomas in mice deficient for both p53 and nonhomologous end-joining (NHEJ) contain complicons that coamplify c-myc (chromosome 15) and IgH (chromosome 12) sequences. While all carry a translocated (12;15) chromosome, coamplified sequences are located within a separate complicon that often involves a third chromosome. Complicon formation is initiated by recombination of RAG1/2-catalyzed IgH locus double-strand breaks with sequences downstream of c-myc, generating a dicentric (15;12) chromosome as an amplification intermediate. This recombination event employs a microhomology-based end-joining repair pathway, as opposed to classic NHEJ or homologous recombination. These findings suggest a general model for oncogenic complicon formation.

KW - Animals

KW - Base Sequence

KW - Chromosomes

KW - DNA Damage

KW - DNA Repair

KW - Gene Amplification

KW - Gene Expression Regulation, Neoplastic

KW - Genes, RAG-1

KW - Genes, myc

KW - In Situ Hybridization, Fluorescence

KW - Lymphoma, B-Cell

KW - Mice

KW - Molecular Sequence Data

KW - RNA, Messenger

KW - Recombination, Genetic

KW - Translocation, Genetic

KW - Tumor Suppressor Protein p53

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, P.H.S.

UR - https://www.scopus.com/pages/publications/0037188898

M3 - Article

C2 - 12110179

SN - 0092-8674

VL - 109

SP - 811

EP - 821

JO - Cell

JF - Cell

IS - 7

ER -

Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations

Abstract

Keywords

UN SDGs

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