The Large Subunit of Replication Factor C Promotes Cell Survival after DNA Damage in an LxCxE Motif– and Rb-Dependent Manner

Pennaneach, Vincent; Salles-Passador, Isabelle; Munshi, Anil; Brickner, Howard; Regazzoni, Karine; Dick, Frederick A.; Dyson, Nicholas J.; Chen, T.-T; Wang, J.Y.J; Fotedar, Rati; Fotedar, Arun

doi:10.1016/s1097-2765(01)00217-9

Cited by 49 publications

(61 citation statements)

References 42 publications

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“…Frag1 has a conserved AAA family motif, a hallmark of the ATPase family associated with various cellular activities, including chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes. Comparison of the mouse and human Frag1 amino acid sequences indicated that they conserve putative Atr-phosphorylation sites (mouse Frag1 at Ser-1150 and Ser-1168 and human Frag1 at Ser-1169 and Ser-1187) (18,19), and a putative Rb binding site with a Leu-x-Cys-x-Glu (LxCxE) motif (amino acids 1409-1413 of mouse and 1428-1432 of human) (20).…”

Section: Resultsmentioning

confidence: 99%

Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis

Ishii

Inageta

Mimori

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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We report the identification and characterization of a potent regulator of genomic integrity, mouse and human FRAG1 gene, a conserved homolog of replication factor C large subunit that is homologous to the alternative replication factor C subunits Elg1, Ctf18͞Chl12, and Rad24 of budding yeast. FRAG1 was identified in a search for key caretaker genes involved in the regulation of genomic stability under conditions of replicative stress. In response to stress, Atr participates in the down-regulation of FRAG1 expression, leading to the induction of apoptosis through the release of Rad9 from damaged chromatin during the S phase of the cell cycle, allowing Rad9 -Bcl2 association and induction of proapoptotic Bax protein. We propose that the Frag1 signal pathway, by linking replication stress surveillance with apoptosis induction, plays a central role in determining whether DNA damage is compatible with cell survival or whether it requires cell elimination by apoptosis.genomic integrity ͉ Bcl2 ͉ Rad9 ͉ Atr ͉ Rb R eplicative stress causes replication fork stalling or arrest, which can occur in yeast at naturally occurring sequences, such as replication fork barriers and replication slow zones (1). When damage is severe or the natural order of DNA replication is perturbed, DNA double-strand breaks can occur (2). Such events can trigger cellular checkpoints, allowing time for repair of damage before cell cycle progression (2). When the breaks are fixed or the damage is compatible with cell survival, double-strand breaks can give rise to the fixed chromosomal aberrations observed in cancer cells, such as translocations, inversions, amplifications, and deletions. Accumulated aberrations of caretaker pathways in concert with alterations of gatekeeper tumor suppressors give rise to transformed cells that acquire selective growth and survival advantages (3). Thus, the pathology of stalled or collapsed replication forks is important for understanding the role of faithful regulation of replication in preventing carcinogenesis.Genotoxic stress-induced replication stalling activates checkpoint-signaling pathways that block cell cycle progression, control DNA repair, or trigger apoptosis (4) through membrane death receptors and the endogenous mitochondrial death pathways (5). Rad9 protein is involved in the control of the DNA damage-induced checkpoint (6). Studies in yeast and human cells have shown that Rad9 interacts with Hus1 and Rad1 in the 9-1-1 complex, which is a heterotrimeric complex and acts as a proliferating cell nuclear antigen-like sliding clamp (4, 7). In response to DNA damage, the 9-1-1 complex is loaded around DNA lesions by Rad17, which binds to chromatin before damage (8) and facilitates Atr-mediated phosphorylation and activation of Chk1 kinase to arrest cell cycle. Rad9 can participate in signaling apoptosis by interacting with antiapoptotic Bcl-2 family proteins Bcl-2 and Bcl-X L but not with proapoptotic Bax and Bad (9). The interaction of Bcl2 with Bax prevents Bax from inducing cytochrome c release and ce...

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Section: Resultsmentioning

confidence: 99%

Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis

Ishii

Inageta

Mimori

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Accordingly, mutation(s) of these contact residues suppressed the ability of Rb to bind LXCXE-containing viral proteins. These Rb mutants retain the ability to bind E2F, repress E2F-1-dependent transcription, and inhibit growth comparable with wild type Rb (26,27) but fail to protect cells from apoptosis (14).…”

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confidence: 97%

“…12). In addition, Rb inhibits cell death induced by DNA-damaging agents (13,14) or E2F-1 (15). The demonstration that Rb null mice die at 13-15 days of gestation accompanied by increased cell death in multiple organs (16 -18) suggests that Rb plays a critical role in regulating apoptosis.…”

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confidence: 99%

“…A conserved LXCXE motif in these viral oncoproteins is critical for their ability to bind Rb (23). Many cellular Rb-binding proteins, which regulate Rb activity including HDAC1 (7), BRG1 (24), and RF-Cp145 (14), contain an LXCXE motif. The three-dimensional crystal structure of the AB pocket of Rb interacting with the LXCXE peptide revealed residues in Rb that contact the LXCXE peptide (25).…”

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confidence: 99%

“…We have previously shown that the LXCXE interaction is critical for the ability of Rb to inhibit cell death induced by a variety of DNA-damaging agents (14). Proteins that bind the LXCXE-binding site in Rb would be expected to regulate the anti-apoptotic activity of Rb.…”

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Rb Inhibits E2F-1-induced Cell Death in a LXCXE-dependent Manner by Active Repression

Pennaneach

Barbier

Regazzoni

et al. 2004

Journal of Biological Chemistry

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The Retinoblastoma Tumour Suppressor

Dirlam¹,

Macleod²

2007

The Cancer Handbook

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The retinoblastoma tumour suppressor (pRB) is functionally inactivated in most human cancers. pRB regulates cell cycle checkpoints, cell death, cellular senescence, and terminal differentiation through interactions with members of the E2F family of transcription factors, chromatin‐remodelling factors and with tissue‐restricted transcription factors. The RB‐related “pocket proteins”, p107 and p130 also interact with E2Fs to regulate cell cycle, although neither p107 nor p130 are known tumour suppressors in human cancer, despite data from mouse models indicating their ability to compensate for Rb loss under certain circumstances. This chapter discusses the latest findings on the role of pRB in development and tumourigenesis to help determine which functions of pRB contribute most to its tumour‐suppressor activity, why certain tumours select against RB but others do not, and what kind of additional mutations are likely to cooperate with RB loss in cancer as a function of tissue type.

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The Large Subunit of Replication Factor C Promotes Cell Survival after DNA Damage in an LxCxE Motif– and Rb-Dependent Manner

Cited by 49 publications

References 42 publications

Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis

Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis

Rb Inhibits E2F-1-induced Cell Death in a LXCXE-dependent Manner by Active Repression

The Retinoblastoma Tumour Suppressor

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