DNA polymerase θ is preferentially expressed in lymphoid tissues and upregulated in human cancers

被引:113
作者
Kawamura, K
Bahar, R
Seimiya, M
Chiyo, M
Wada, A
Okada, S
Hatano, M
Tokuhisa, T
Kimura, H
Watanabe, S
Honda, I
Sakiyama, S
Tagawa, M
O-Wang, JY
机构
[1] Chiba Canc Ctr, Res Inst, Div Pathol, Chuo Ku, Chiba 2608717, Japan
[2] RIKEN, Yokohama Inst, Res Ctr Allergy & Immunol, Lab B Lymphocyte Funct, Yokohama, Kanagawa, Japan
[3] Childrens Canc Res Inst, Div Gastroenterol Surg, Chiba, Japan
[4] Childrens Canc Res Inst, Div Thorac Dis, Chiba, Japan
[5] Chiba Univ, Grad Sch Med, Dept Dev Genet, Chiba, Japan
[6] Kumamoto Univ, Ctr AIDS Res, Div Hemopoiesis, Kumamoto, Japan
关键词
genomic instability; gene recombination; tumorigenesis; clinical prognosis; immune system;
D O I
10.1002/ijc.11666
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
DNA polymerase theta (Pol theta) is a recently identified family A polymerase that contains an intrinsic helicase domain. Drosophila Pol theta mutants are hypersensitive to bifunctional DNA crosslinking agents and exhibit an elevated frequency of spontaneous chromosomal aberrations, suggesting a role for Poll theta in repair of DNA interstrand crosslinks and in the general maintenance of genome stability. To investigate a possible involvement of Pol theta in tumorigenesis, we have examined its expression in various normal and malignant tissues. Paired tumor and adjacent nontumorous tissues from patients with lung (n = 27), stomach (n = 28) and colon (n = 26) cancer, as well as 26 normal human tissues, were examined for Pol theta expression by RT-PCR, Northern or Western blot analysis. Poll theta was predominantly expressed in primary lymphoid organs including the fetal liver, thymus and bone marrow where lymphocyte progenitors undergo V(D)J rearrangements of their antigen receptor genes. In addition, Pol theta expression was upregulated in germinal center B cells, in which class switch recombination of the immunoglobulin genes occurs. Examination of Pol theta expression in matched cancer specimens revealed that Pol theta was barely detectable in the nontumorous tissues but was upregulated in 17 of 27 (63%) lung, 11 of 28 (39%) stomach and 20 of 26 (77%) colon cancers. Moreover, patients with high levels of Pol theta expression had a significantly poorer clinical outcome compared with those expressing low levels of Pol theta. These results implicate that Pol theta may have a specialized function in lymphocytes and that its overexpression may contribute to tumor progression. (C) 2003 Wiley-Liss, Inc.
引用
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页码:9 / 16
页数:8
相关论文
共 35 条
[1]  
BOYD JB, 1990, GENETICS, V125, P813
[2]   TUMORIGENICITY OF OPTICAL ENANTIOMERS OF DIASTEREOMERIC BENZO[A]PYRENE 7,8-DIOL-9,10-EPOXIDES IN NEWBORN MICE - EXCEPTIONAL ACTIVITY OF(+)-7-BETA, 8-ALPHA-DIHYDROXY-9-ALPHA, 10-ALPHA-EPOXY-7,8.9.10-TETRAHYDROBENZOL[A]PYRENE [J].
BUENING, MK ;
WISLOCKI, PG ;
LEVIN, W ;
YAGI, H ;
THAKKER, DR ;
AKAGI, H ;
KOREEDA, M ;
JERINA, DM ;
CONNEY, AH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1978, 75 (11) :5358-5361
[3]   DNA polymerase mu (Pol μ), homologous to TdT, could act as a DNA mutator in eukaryotic cells [J].
Domínguez, O ;
Ruiz, JF ;
de Lera, TL ;
García-Díaz, M ;
González, MA ;
Kirchhoff, T ;
Martínez-A, C ;
Bernad, A ;
Blanco, L .
EMBO JOURNAL, 2000, 19 (07) :1731-1742
[4]   In situ class switching and differentiation to IgA-producing cells in the gut lamina propria [J].
Fagarasan, S ;
Kinoshita, K ;
Muramatsu, M ;
Ikuta, K ;
Honjo, T .
NATURE, 2001, 413 (6856) :639-643
[5]   Molecular biology - Specialized DNA polymerases, cellular survival, and the genesis of mutations [J].
Friedberg, EC ;
Wagner, R ;
Radman, M .
SCIENCE, 2002, 296 (5573) :1627-1630
[6]   RESOLUTION AND CHARACTERIZATION OF PRO-B AND PRE-PRO-B CELL STAGES IN NORMAL MOUSE BONE-MARROW [J].
HARDY, RR ;
CARMACK, CE ;
SHINTON, SA ;
KEMP, JD ;
HAYAKAWA, K .
JOURNAL OF EXPERIMENTAL MEDICINE, 1991, 173 (05) :1213-1225
[7]  
Harris PV, 1996, MOL CELL BIOL, V16, P5764
[8]   Genome maintenance mechanisms for preventing cancer [J].
Hoeijmakers, JHJ .
NATURE, 2001, 411 (6835) :366-374
[9]   Eukaryotic DNA polymerases [J].
Hübscher, U ;
Maga, G ;
Spadari, S .
ANNUAL REVIEW OF BIOCHEMISTRY, 2002, 71 :133-163
[10]   INTRACLONAL GENERATION OF ANTIBODY MUTANTS IN GERMINAL-CENTERS [J].
JACOB, J ;
KELSOE, G ;
RAJEWSKY, K ;
WEISS, U .
NATURE, 1991, 354 (6352) :389-392