BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer.
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.
Rai
Rekha
R
Department of Molecular Therapeutics, The University of Texas M D Anderson Cancer Center, Houston, Texas 77054, USA.
Dai
Hui
H
Multani
Asha S
AS
Li
Kaiyi
K
Chin
Koei
K
Gray
Joe
J
Lahad
John P
JP
Liang
Jiyong
J
Mills
Gordon B
GB
Meric-Bernstam
Funda
F
Lin
Shiaw-Yih
SY
D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D002843:Chromatin / Q000378:metabolism; D002869:Chromosome Aberrations; D003598:Cytoskeletal Proteins; D004249:DNA Damage; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; D002843:Chromatin; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins