DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes

Ofir Hakim; Wolfgang Resch; Arito Yamane; Isaac Klein; Kyong Rim Kieffer-Kwon; Mila Jankovic; Thiago Oliveira; Anne Bothmer; Ty C. Voss; Camilo Ansarah-Sobrinho; Ewy Mathe; Genqing Liang; Jesse Cobell; Hirotaka Nakahashi; Davide F. Robbiani; Andre Nussenzweig; Gordon L. Hager; Michel C. Nussenzweig; Rafael Casellas

doi:10.1038/nature10909

DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes

Ofir Hakim
, Wolfgang Resch
, Arito Yamane
, Isaac Klein
, Kyong Rim Kieffer-Kwon
, Mila Jankovic
, Thiago Oliveira
, Anne Bothmer
, Ty C. Voss
, Camilo Ansarah-Sobrinho
, Ewy Mathe
, Genqing Liang
, Jesse Cobell
, Hirotaka Nakahashi
, Davide F. Robbiani
, Andre Nussenzweig
, Gordon L. Hager
, Michel C. Nussenzweig
, Rafael Casellas

National Institutes of Health
Rockefeller University
Universidade de São Paulo

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

183 Scopus citations

Abstract

Recurrent chromosomal translocations underlie both haematopoietic and solid tumours. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners; however, the relative contribution of each of these elements has not been measured directly or on a large scale. Here we examine the role of nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured mouse B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or Myc and all other genes are directly related to their contact frequency. Conversely, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA break formation, as measured by replication protein A accumulation at the site of damage. Thus, non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent translocations, including those driving B-cell malignancies.

Original language	English
Pages (from-to)	69-74
Number of pages	6
Journal	Nature
Volume	484
Issue number	7392
DOIs	https://doi.org/10.1038/nature10909
State	Published - 5 Apr 2012
Externally published	Yes

Bibliographical note

Funding Information:
Acknowledgements We thank members of the Casellas and Nussenzweig laboratories for discussions; G. Gutierrez from NIAMS genomics facility for technical assistance. This work was supported in part by a grant from the Starr Foundation to M.C.N., by NIH grantnumberAI037526toM.C.N.and the IntramuralResearchProgram ofNIAMS and NCI, NIH. M.C.N. is an HHMI investigator. This study made use of the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http:// biowulf.nih.gov), and the resources of NCI’s High-Throughput Imaging Facility.

Funding

Acknowledgements We thank members of the Casellas and Nussenzweig laboratories for discussions; G. Gutierrez from NIAMS genomics facility for technical assistance. This work was supported in part by a grant from the Starr Foundation to M.C.N., by NIH grantnumberAI037526toM.C.N.and the IntramuralResearchProgram ofNIAMS and NCI, NIH. M.C.N. is an HHMI investigator. This study made use of the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http:// biowulf.nih.gov), and the resources of NCI’s High-Throughput Imaging Facility.

Funders	Funder number
National Institutes of Health
National Cancer Institute	ZIABC010959
Starr Foundation

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10.1038/nature10909

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Hakim, O., Resch, W., Yamane, A., Klein, I., Kieffer-Kwon, K. R., Jankovic, M., Oliveira, T., Bothmer, A., Voss, T. C., Ansarah-Sobrinho, C., Mathe, E., Liang, G., Cobell, J., Nakahashi, H., Robbiani, D. F., Nussenzweig, A., Hager, G. L., Nussenzweig, M. C., & Casellas, R. (2012). DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes. Nature, 484(7392), 69-74. https://doi.org/10.1038/nature10909

@article{b32250a84e6046dc8ee5460a7507cbcc,

title = "DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes",

abstract = "Recurrent chromosomal translocations underlie both haematopoietic and solid tumours. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners; however, the relative contribution of each of these elements has not been measured directly or on a large scale. Here we examine the role of nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured mouse B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or Myc and all other genes are directly related to their contact frequency. Conversely, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA break formation, as measured by replication protein A accumulation at the site of damage. Thus, non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent translocations, including those driving B-cell malignancies.",

author = "Ofir Hakim and Wolfgang Resch and Arito Yamane and Isaac Klein and Kieffer-Kwon, \{Kyong Rim\} and Mila Jankovic and Thiago Oliveira and Anne Bothmer and Voss, \{Ty C.\} and Camilo Ansarah-Sobrinho and Ewy Mathe and Genqing Liang and Jesse Cobell and Hirotaka Nakahashi and Robbiani, \{Davide F.\} and Andre Nussenzweig and Hager, \{Gordon L.\} and Nussenzweig, \{Michel C.\} and Rafael Casellas",

note = "Funding Information: Acknowledgements We thank members of the Casellas and Nussenzweig laboratories for discussions; G. Gutierrez from NIAMS genomics facility for technical assistance. This work was supported in part by a grant from the Starr Foundation to M.C.N., by NIH grantnumberAI037526toM.C.N.and the IntramuralResearchProgram ofNIAMS and NCI, NIH. M.C.N. is an HHMI investigator. This study made use of the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http:// biowulf.nih.gov), and the resources of NCI{\textquoteright}s High-Throughput Imaging Facility.",

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Hakim, O, Resch, W, Yamane, A, Klein, I, Kieffer-Kwon, KR, Jankovic, M, Oliveira, T, Bothmer, A, Voss, TC, Ansarah-Sobrinho, C, Mathe, E, Liang, G, Cobell, J, Nakahashi, H, Robbiani, DF, Nussenzweig, A, Hager, GL, Nussenzweig, MC & Casellas, R 2012, 'DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes', Nature, vol. 484, no. 7392, pp. 69-74. https://doi.org/10.1038/nature10909

TY - JOUR

T1 - DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes

AU - Hakim, Ofir

AU - Resch, Wolfgang

AU - Yamane, Arito

AU - Klein, Isaac

AU - Kieffer-Kwon, Kyong Rim

AU - Jankovic, Mila

AU - Oliveira, Thiago

AU - Bothmer, Anne

AU - Voss, Ty C.

AU - Ansarah-Sobrinho, Camilo

AU - Mathe, Ewy

AU - Liang, Genqing

AU - Cobell, Jesse

AU - Nakahashi, Hirotaka

AU - Robbiani, Davide F.

AU - Nussenzweig, Andre

AU - Hager, Gordon L.

AU - Nussenzweig, Michel C.

AU - Casellas, Rafael

N1 - Funding Information: Acknowledgements We thank members of the Casellas and Nussenzweig laboratories for discussions; G. Gutierrez from NIAMS genomics facility for technical assistance. This work was supported in part by a grant from the Starr Foundation to M.C.N., by NIH grantnumberAI037526toM.C.N.and the IntramuralResearchProgram ofNIAMS and NCI, NIH. M.C.N. is an HHMI investigator. This study made use of the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http:// biowulf.nih.gov), and the resources of NCI’s High-Throughput Imaging Facility.

PY - 2012/4/5

Y1 - 2012/4/5

N2 - Recurrent chromosomal translocations underlie both haematopoietic and solid tumours. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners; however, the relative contribution of each of these elements has not been measured directly or on a large scale. Here we examine the role of nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured mouse B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or Myc and all other genes are directly related to their contact frequency. Conversely, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA break formation, as measured by replication protein A accumulation at the site of damage. Thus, non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent translocations, including those driving B-cell malignancies.

AB - Recurrent chromosomal translocations underlie both haematopoietic and solid tumours. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners; however, the relative contribution of each of these elements has not been measured directly or on a large scale. Here we examine the role of nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured mouse B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or Myc and all other genes are directly related to their contact frequency. Conversely, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA break formation, as measured by replication protein A accumulation at the site of damage. Thus, non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent translocations, including those driving B-cell malignancies.

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AN - SCOPUS:84859474968

SN - 0028-0836

VL - 484

SP - 69

EP - 74

JO - Nature

JF - Nature

IS - 7392

ER -

DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes

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Bibliographical note

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