Dimerization of the ATRIP protein through the coiled-coil motif and its implication to the maintenance of stalled replication forks

被引：35

作者：

Itakura, E ^{[1
]}

Sawada, I ^{[1
]}

Matsuura, A ^{[1
]}

机构：

[1] Natl Ctr Geriatr & Gerontol, Natl Inst Longevity Sci, Dept Geriatr Med, Aichi 4748522, Japan

来源：

MOLECULAR BIOLOGY OF THE CELL | 2005年 / 16卷 / 12期

关键词：

D O I：

10.1091/mbc.E05-05-0427

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

ATR (ATM and Rad3-related), a PI kinase-related kinase (PIKK), has been implicated in the DNA structure checkpoint in mammalian cells. ATR associates with its partner protein ATRIP to form a functional complex in the nucleus. In this study, we investigated the role of the ATRIP coiled-coil domain in ATR-mediated processes. The coiled-coil domain of human ATRIP contributes to self-dimerization in vivo, which is important for the stable translocation of the ATR-ATRIP complex to nuclear foci that are formed after exposure to genotoxic stress. The expression of dimerization-defective ATRIP diminishes the maintenance of replication forks during treatment with replication inhibitors. By contrast, it does not compromise the G2/M checkpoint after IR-induced DNA damage. These results show that there are two critical functions of ATR-ATRIP after the exposure to genotoxic stress: maintenance of the integrity of replication machinery and execution of cell cycle arrest, which are separable and are achieved via distinct mechanisms. The former function may involve the concentrated localization of ATR to damaged sites for which the ATRIP coiled-coil motif is critical.

引用

页码：5551 / 5562

页数：12

共 67 条

[11] Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance [J].

Brown, EJ ;

Baltimore, D .

GENES & DEVELOPMENT, 2003, 17 (05) :615-628

[12] Mutation of the mouse Rad17 gene leads to embryonic lethality and reveals a role in DNA damage-dependent recombination [J].

Budzowska, M ;

Jaspers, I ;

Essers, J ;

de Waard, H ;

van Drunen, E ;

Hanada, K ;

Beverloo, B ;

Hendriks, RW ;

de Klein, A ;

Kanaar, R ;

Hoeijmakers, JH ;

Maas, A .

EMBO JOURNAL, 2004, 23 (17) :3548-3558

[13] ATR regulates fragile site stability [J].

Casper, AM ;

Nghiem, P ;

Arlt, MF ;

Glover, TW .

CELL, 2002, 111 (06) :779-789

[14] Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks [J].

Celeste, A ;

Fernandez-Capetillo, O ;

Kruhlak, MJ ;

Pilch, DR ;

Staudt, DW ;

Lee, A ;

Bonner, RF ;

Bonner, WM ;

Nussenzweig, A .

NATURE CELL BIOLOGY, 2003, 5 (07) :675-U51

[15] ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones [J].

Cha, RS ;

Kleckner, N .

SCIENCE, 2002, 297 (5581) :602-606

[16] DNA polymerase stabilization at stalled replication forks requires Mec1 and the RecQ helicase Sgs1 [J].

Cobb, JA ;

Bjergbaek, L ;

Shimada, K ;

Frei, C ;

Gasser, SM .

EMBO JOURNAL, 2003, 22 (16) :4325-4336

[17] ATR and ATRIP: Partners in checkpoint signaling [J].

Cortez, D ;

Guntuku, S ;

Qin, J ;

Elledge, SJ .

SCIENCE, 2001, 294 (5547) :1713-1716

[18] Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases [J].

Cortez, D ;

Glick, G ;

Elledge, SJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (27) :10078-10083

[19] Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase [J].

Dart, DA ;

Adams, KE ;

Akerman, I ;

Lakin, ND .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (16) :16433-16440

[20] Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice [J].

de Klein, A ;

Muijtjens, M ;

van Os, R ;

Verhoeven, Y ;

Smit, B ;

Carr, AM ;

Lehmann, AR ;

Hoeijmakers, JHJ .

CURRENT BIOLOGY, 2000, 10 (08) :479-482

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