HsRec2/Rad51L1, a Protein Influencing Cell Cycle Progression, Has Protein Kinase Activity

Havre, Pamela A.; Rice, Michael C.; Ramos, R. Argotte; Kmiec, Eric B.

doi:10.1006/excr.1999.4725

Cited by 22 publications

(12 citation statements)

References 44 publications

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“…It seems likely that the human Rad51-paralogs play a role in the formation of HsRad51/ssDNA filaments, although even if they do, they may have additional functions. For example, it has recently been reported that Rad51B (HsRec2/Rad51L1) has protein kinase activity (42).…”

Section: Discussionmentioning

confidence: 99%

Evidence for Simultaneous Protein Interactions between Human Rad51 Paralogs

Schild

Lio

Collins

et al. 2000

Journal of Biological Chemistry

181

152

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In yeast, the Rad51-related proteins include Rad55 and Rad57, which form a heterodimer that interacts with Rad51. Five human Rad51 paralogs have been identified (XRCC2, XRCC3, Rad51B/Rad51L1, Rad51C/ Rad51L2, and Rad51D/Rad51L3), and each interacts with one or more of the others. Previously we reported that HsRad51 interacts with XRCC3, and Rad51C interacts with XRCC3, Rad51B, and HsRad51. Here we report that in the yeast two-hybrid system, Rad51D interacts with XRCC2 and Rad51C. No other interactions, including self-interactions, were found, indicating that the observed interactions are specific. The yeast Rad51 interacts with human Rad51 and XRCC3, suggesting Rad51 conservation since the human yeast divergence. Data from yeast three-hybrid experiments indicate that a number of the pairs of interactions between human Rad51 paralogs can occur simultaneously. For example, Rad51B expression enhances the binding of Rad51C to XRCC3 and to HsRad51D, and Rad51C expression allows the indirect interaction of Rad51B with Rad51D. Experiments using 6xHis-tagged proteins in the baculovirus system confirm several of our yeast results, including Rad51B interaction with Rad51D only when Rad51C is simultaneously expressed and Rad51C interaction with XRCC2 only when Rad51D is present. These results suggest that these proteins may participate in one complex or multiple smaller ones.The Rad51 protein is a functional homolog of the bacterial RecA protein and is the major strand transfer protein in eucaryotic cells (1-3). In addition to Rad51, the yeast Saccharomyces cerevisiae has two proteins, Rad55 and Rad57, that share limited amino acid sequence homology with Rad51. These proteins appear to be Rad51 paralogs, probably derived by duplication of the ancestral gene encoding Rad51 but now divergent in function. The Rad55 and Rad57 proteins interact and form a tight dimer that weakly interacts with Rad51 and assists it in strand transfer, probably by helping Rad51 displace RPA from single-stranded DNA (4).Human cells have a true Rad51 homolog (HsRad51), and five mitotically expressed Rad51 paralogs have recently been identified (XRCC2, XRCC3, Rad51B/Rad51L1/HsRec2, Rad51C/ Rad51L2, and Rad51D/Rad51L3) (5-11). Like the yeast Rad51 paralogs, these proteins share limited (ϳ20 -30%) amino acid sequence homology with HsRad51 and with each other. The human XRCC2 and XRCC3 genes were isolated (5, 6, 12) and shown to complement the DNA repair defect and chromosome instability of the irs1 and irs1SF hamster-derived cell lines (13-16). Each of the paralogs has recently been knocked out in the chicken B lymphocyte line DT40, and all of the knockouts are sensitive to DNA damage and show great chromosome instability (17). 1Several lines of evidence suggest that the human Rad51 paralogs play an important, but not crucial, role in recombination. Evidence from mammalian cells indicates that the repair of DNA cross-links requires recombination (18,19). The extreme sensitivity to DNA cross-linking reagents, such as mitomycin C and cis-platin, of mamm...

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Section: Discussionmentioning

confidence: 99%

Evidence for Simultaneous Protein Interactions between Human Rad51 Paralogs

Schild

Lio

Collins

et al. 2000

Journal of Biological Chemistry

181

152

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“…Although the RAD51L1 protein has not yet been shown to catalyze recombination reactions, RAD51L1 appears to be an essential gene (Shu et al 1999) expressed in almost all organs and tissues (Rice et al 1997) and probably plays a role in regulation of cell cycle progression (Havre et al 1998(Havre et al , 2000. In view of the purported function of HMGIC in regulation of cell proliferation (Reeves 2000) and the probable role of RAD51L1 in cell cycle regulation, it is reasonable to speculate that the disruption of genomic structure associated with the RAD51L1/HMGIC fusion (Ingraham et al 1999;Schoenmakers et al 1999;Takahashi et al 2001) might result in dysregulated cell growth.…”

Section: The Genetic Findingsmentioning

confidence: 99%

Etiology and pathogenesis of uterine leiomyomas: a review.

Flake

Andersen

Dixon

2003

Environ Health Perspect

497

392

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Uterine leiomyomas, or fibroids, represent a major public health problem. It is believed that these tumors develop in the majority of American women and become symptomatic in one-third of these women. They are the most frequent indication for hysterectomy in the United States. Although the initiator or initiators of fibroids are unknown, several predisposing factors have been identified, including age (late reproductive years), African-American ethnicity, nulliparity, and obesity. Nonrandom cytogenetic abnormalities have been found in about 40% of tumors examined. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has only recently been explored. Growth factors with mitogenic activity, such as transforming growth factor-β 3, basic fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I, are elevated in fibroids and may be the effectors of estrogen and progesterone promotion. These data offer clues to the etiology and pathogenesis of this common condition, which we have analyzed and summarized in this review.

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“…HCMVstimulated CD69 ϩ and CD69 Ϫ monoclonal CD4 ϩ T-LGL showed typical traits of an inflammatory response associated with an increased expression of the CCL8, CXCL10, TNFAIP6, and SOD2 genes involved in chemotaxis, cell-cell interactions, and the oxidative stress during inflammation [23][24][25][26] (Figure 2). Likewise, these cells acquired a quiescent phenotype as reflected by a decreased expression of the KIAA999 and PRIM2A enzymes in association with overexpression of the RAD51L1, CAPNS2, TFEC, and C15orf48 genes, a gene expression profile presumably reflecting an arrest or a delay in cell-cycle progression [27][28][29][30][31] (Figure 2). In addition, hCMV stimulation of monoclonal CD4 ϩ T cells could also lead to an increased resistance to apoptosis resulting from down-regulation of the proapoptotic PTGDS gene and overexpression of the antiapoptotic SOD2 gene.…”

Section: Figure 1 Functional Response To Hcmv In Patients With Monocmentioning

confidence: 99%