BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer

Rekha Rai; Hui Dai; Asha S. Multani; Kaiyi Li; Koei Chin; Joe Gray; John P. Lahad; Jiyong Liang; Gordon B. Mills; Funda Meric-Bernstam; Shiaw Yih Lin

doi:10.1016/j.ccr.2006.07.002

BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer

Rekha Rai
, Hui Dai
, Asha S. Multani
, Kaiyi Li
, Koei Chin
, Joe Gray
, John P. Lahad
, Jiyong Liang
, Gordon B. Mills
, Funda Meric-Bernstam
, Shiaw Yih Lin

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

136 Scopus citations

Abstract

BRIT1, initially identified as an hTERT repressor, has additional functions at DNA damage checkpoints. Here, we demonstrate that BRIT1 formed nuclear foci minutes after irradiation. The foci of BRIT1 colocalized with 53BP1, MDC1, NBS1, ATM, RPA, and ATR. BRIT1 was required for activation of these elements, indicating that BRIT1 is a proximal factor in the DNA damage response pathway. Depletion of BRIT1 increased the accumulation of chromosomal aberrations. In addition, decreased levels of BRIT1 were detected in several types of human cancer, with BRIT1 expression being inversely correlated with genomic instability and metastasis. These results identify BRIT1 as a crucial DNA damage regulator in the ATM/ATR pathways and suggest that it functions as a tumor suppressor gene.

Original language	English (US)
Pages (from-to)	145-157
Number of pages	13
Journal	Cancer Cell
Volume	10
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2006.07.002
State	Published - Jan 1 2006
Externally published	Yes

Funding

We thank Dr. Z.-X. Xu for the initial assistance on the nuclear foci staining and Christine Wogan of the Department of Scientific Publications for editorial assistance and the Cytogenetics Core at the M.D. Anderson Cancer Center. We also thank Dr. Andrew Jackson (MRC Human Genetics Unit, Western General Hospital) for sharing critical unpublished data on microcephaly. This work was supported by NCI grant R01 CA112291-01A1 and by institutional funds from The University of Texas M.D. Anderson Cancer Center to S.-Y.L. and by NIH grants P50 CA83639 and P01 CA64602 to G.B.M.

Funders	Funder number
Department of Scientific Publications
M.D. Anderson Cancer Center
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	P01 CA64602, P50 CA83639
National Institute of Health-National Cancer Institute	R01 CA112291-01A1, U54CA112970
University of Texas M.D. Anderson Cancer Center
Medical Research Council/Biological Sciences Research Council
Imaging and Morphology Core and Endocrine Technologies Support Core
Western University

Keywords

DNA

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2006.07.002

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title = "BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer",

abstract = "BRIT1, initially identified as an hTERT repressor, has additional functions at DNA damage checkpoints. Here, we demonstrate that BRIT1 formed nuclear foci minutes after irradiation. The foci of BRIT1 colocalized with 53BP1, MDC1, NBS1, ATM, RPA, and ATR. BRIT1 was required for activation of these elements, indicating that BRIT1 is a proximal factor in the DNA damage response pathway. Depletion of BRIT1 increased the accumulation of chromosomal aberrations. In addition, decreased levels of BRIT1 were detected in several types of human cancer, with BRIT1 expression being inversely correlated with genomic instability and metastasis. These results identify BRIT1 as a crucial DNA damage regulator in the ATM/ATR pathways and suggest that it functions as a tumor suppressor gene.",

keywords = "DNA",

author = "Rekha Rai and Hui Dai and Multani, \{Asha S.\} and Kaiyi Li and Koei Chin and Joe Gray and Lahad, \{John P.\} and Jiyong Liang and Mills, \{Gordon B.\} and Funda Meric-Bernstam and Lin, \{Shiaw Yih\}",

note = "Funding Information: We thank Dr. Z.-X. Xu for the initial assistance on the nuclear foci staining and Christine Wogan of the Department of Scientific Publications for editorial assistance and the Cytogenetics Core at the M.D. Anderson Cancer Center. We also thank Dr. Andrew Jackson (MRC Human Genetics Unit, Western General Hospital) for sharing critical unpublished data on microcephaly. This work was supported by NCI grant R01 CA112291-01A1 and by institutional funds from The University of Texas M.D. Anderson Cancer Center to S.-Y.L. and by NIH grants P50 CA83639 and P01 CA64602 to G.B.M. ",

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doi = "10.1016/j.ccr.2006.07.002",

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AU - Rai, Rekha

AU - Dai, Hui

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AU - Chin, Koei

AU - Gray, Joe

AU - Lahad, John P.

AU - Liang, Jiyong

AU - Mills, Gordon B.

AU - Meric-Bernstam, Funda

AU - Lin, Shiaw Yih

N1 - Funding Information: We thank Dr. Z.-X. Xu for the initial assistance on the nuclear foci staining and Christine Wogan of the Department of Scientific Publications for editorial assistance and the Cytogenetics Core at the M.D. Anderson Cancer Center. We also thank Dr. Andrew Jackson (MRC Human Genetics Unit, Western General Hospital) for sharing critical unpublished data on microcephaly. This work was supported by NCI grant R01 CA112291-01A1 and by institutional funds from The University of Texas M.D. Anderson Cancer Center to S.-Y.L. and by NIH grants P50 CA83639 and P01 CA64602 to G.B.M.

PY - 2006/1/1

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AB - BRIT1, initially identified as an hTERT repressor, has additional functions at DNA damage checkpoints. Here, we demonstrate that BRIT1 formed nuclear foci minutes after irradiation. The foci of BRIT1 colocalized with 53BP1, MDC1, NBS1, ATM, RPA, and ATR. BRIT1 was required for activation of these elements, indicating that BRIT1 is a proximal factor in the DNA damage response pathway. Depletion of BRIT1 increased the accumulation of chromosomal aberrations. In addition, decreased levels of BRIT1 were detected in several types of human cancer, with BRIT1 expression being inversely correlated with genomic instability and metastasis. These results identify BRIT1 as a crucial DNA damage regulator in the ATM/ATR pathways and suggest that it functions as a tumor suppressor gene.

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BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer

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Keywords

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