Dynamic Changes of BRCA1 Subnuclear Location and Phosphorylation State Are Initiated by DNA Damage

Scully, Ralph; Chen, Junjie; Ochs, Robert; Keegan, Kathleen; Hoekstra, Merl F.; Feunteun, Jean; Livingston, David M.

doi:10.1016/s0092-8674(00)80503-6

Cited by 859 publications

(790 citation statements)

References 52 publications

Supporting

Mentioning

738

Contrasting

Unclassified

Order By: Relevance

“…To our knowledge, RAD51 has not been identified outside of plants as a possible target of CDKs under DNA damage conditions. However, animal RAD51 also contains a consensus CDK phosphorylation site S/T‐X‐R/K and it has been previously observed in animals and yeast that the formation of Rad51 foci after DNA damage indirectly depends on CDK activity via BRCA1 and BRCA2 (Scully et al , 1997; Ira et al , 2004; Johnson et al , 2009; Quennet et al , 2011). At least in plants, recruitment of RAD51 to damaged DNA might not only be an indication for HR but could directly be dependent on CDK activity.…”

Section: Discussionmentioning

confidence: 99%

The plant‐specific CDKB 1‐ CYCB 1 complex mediates homologous recombination repair in Arabidopsis

et al. 2016

View full text Add to dashboard Cite

Upon DNA damage, cyclin‐dependent kinases (CDKs) are typically inhibited to block cell division. In many organisms, however, it has been found that CDK activity is required for DNA repair, especially for homology‐dependent repair (HR), resulting in the conundrum how mitotic arrest and repair can be reconciled. Here, we show that Arabidopsis thaliana solves this dilemma by a division of labor strategy. We identify the plant‐specific B1‐type CDKs (CDKB1s) and the class of B1‐type cyclins (CYCB1s) as major regulators of HR in plants. We find that RADIATION SENSITIVE 51 (RAD51), a core mediator of HR, is a substrate of CDKB1‐CYCB1 complexes. Conversely, mutants in CDKB1 and CYCB1 fail to recruit RAD51 to damaged DNA. CYCB1;1 is specifically activated after DNA damage and we show that this activation is directly controlled by SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1), a transcription factor that acts similarly to p53 in animals. Thus, while the major mitotic cell‐cycle activity is blocked after DNA damage, CDKB1‐CYCB1 complexes are specifically activated to mediate HR.

show abstract

Section: Discussionmentioning

confidence: 99%

The plant‐specific CDKB 1‐ CYCB 1 complex mediates homologous recombination repair in Arabidopsis

et al. 2016

View full text Add to dashboard Cite

show abstract

“…BRCA1 normally colocalizes with Rad51, the human homologue of the Escherichia coli RecA protein, at nuclear dot structures that may be sites of checkpoint processing in S phase cells (Scully et al, 1997c;Tashiro et al, 1996). Following exposure to DNA damaging agents, BRCA1 becomes hyperphosphorylated and disperses from dot structures and then dynamically accumulates at PCNA-containing replication structures, suggesting a role in the checkpoint response (Scully et al, 1997b).…”

Section: Introductionmentioning

confidence: 99%

“…Several properties of BRCA1 and p53 suggest that these two proteins may functionally interact. Both p53 and BRCA1 are tumor suppressor genes that have been implicated in DNA damage response and repair pathways (Levine, 1997;Scully et al, 1997b;Brugarolas and Jacks, 1997). Both p53 and BRCA1 are physically-altered by the cellular response to DNA damage, p53 by stabilization and BRCA1 by hyperphosphorylation (Kastan et al, 1991;Scully et al, 1997b).…”

Section: Introductionmentioning

confidence: 99%

“…Both p53 and BRCA1 are tumor suppressor genes that have been implicated in DNA damage response and repair pathways (Levine, 1997;Scully et al, 1997b;Brugarolas and Jacks, 1997). Both p53 and BRCA1 are physically-altered by the cellular response to DNA damage, p53 by stabilization and BRCA1 by hyperphosphorylation (Kastan et al, 1991;Scully et al, 1997b). Both p53 and BRCA1 can activate p21 as a common target gene (El-Deiry et al, 1993;Somasundaram et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

BRCA1 physically associates with p53 and stimulates its transcriptional activity

et al. 1998

View full text Add to dashboard Cite

Mutations of the BRCA1 tumor suppressor gene are the most commonly detected alterations in familial breast and ovarian cancer. Although BRCA1 is required for normal mouse development, the molecular basis for its tumor suppressive function remains poorly understood. We show here that BRCA1 increases p53-dependent transcription from the p21 WAF1/CIP1 and bax promoters. We also show that BRCA1 and p53 proteins interact both in vitro and in vivo. The interacting regions map, in vitro, to aa 224 ± 500 of BRCA1 and the C-terminal domain of p53. Tumor-derived transactivation-de®cient BRCA1 mutants are defective in co-activation of p53-dependent transcription and a truncation mutant of BRCA1 that retains the p53-interacting region acts as a dominant inhibitor of p53-dependent transcription. BRCA1 and p53 cooperatively induce apoptosis of cancer cells. The results indicate that BRCA1 and p53 may coordinately regulate gene expression in their role as tumor suppressors.

show abstract

“…The Nbs1/γ-H2AX/Brca1/Rad51 nuclear foci observed in activated B cells may represent repair-complex storage sites, replication-associated DNA damage 8 , telomeric complexes 9 , or a specific response to CSR-induced breaks. To determine whether Nbs1/γ-H2AX/Brca1/ Rad51 foci are associated with sites of CSR, we performed immunocytochemistry staining followed by fluorescence in situ hybridization (ICC-FISH) to simultaneously visualize DNA (IgH, TCRα, or immuoglobulin light chain (Igκ) loci) and protein (Nbs1, γ-H2AX, Brca1 or Rad51) in lymphocytes stimulated with LPS and IL-4 ( Fig.…”

mentioning

confidence: 99%

AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching

Petersen

Casellas

Reina‐San‐Martin

et al. 2001

Nature

463

438

View full text Add to dashboard Cite

Class switch recombination (CSR) is a region-specific DNA recombination reaction that replaces one immunoglobulin heavy-chain constant region (CH) gene with another. This enables a single variable (V) region gene to be used in conjunction with different downstream CH genes, each having a unique biological activity. The molecular mechanisms that mediate CSR have not been defined, but activation-induced cytidine deaminase (AID), a putative RNA-editing enzyme, is required for this reaction 1 . Here we report that the Nijmegen breakage syndrome protein (Nbs1) and phosphorylated H2A histone family member X (γ-H2AX, also known as γ-H2afx), which facilitate DNA double-strand break (DSB) repair 2-4 , form nuclear foci at the CH region in the G1 phase of the cell cycle in cells undergoing CSR, and that switching is impaired in H2AX -/-mice. Localization of Nbs1 and γ-H2AX to the IgH locus during CSR is dependent on AID. In addition, AID is required for induction of switch region (Sμ)-specific DNA lesions that precede CSR. These results place AID function upstream of the DNA modifications that initiate CSR.Correspondence and requests for materials should be addressed to A.N. (andre_nussenzweig@nih.gov) or M.C.N. (nussen@mail.rockefeller.edu).. Supplementary Information accompanies the paper on Nature's website (http://www.nature.com). Competing interests statementThe authors declare that they have no competing financial interests. To determine whether DNA repair factors associate with DSBs at the switch regions, we first examined the intracellular localization of γ-H2AX, Nbs1, Rad51 and Brca1 in activated B cells by immunofluorescence. Brca1 and Rad51 are required for homologous recombination, the Mre11-Rad50-Nbs1 complex has been implicated in both homologous recombination and non-homologous end-joining (NHEJ), and γ-H2AX is critical for recruiting these repair factors to DSBs 6 and facilitates NHEJ in Saccharomyces cerevisiae 4 . All four proteins showed diffuse nuclear staining in most of the resting B cells from C57BL/6 wild-type mice. High local concentrations of these factors (nuclear foci) were detected in a very small percentage of cells (<5%), which increased significantly when the cells were stimulated to undergo CSR in vitro with lipopolysaccharide (LPS) and interleukin (IL)-4 (Fig. 1a). After 3 days of stimulation, 37% of the B cells contained discrete Brca1 foci (12 ± 6 per cell) and 43% contained Rad51 foci (7 ± 3 per cell), consistent with previous results 7 ; the remaining cells exhibited a weak, diffuse pattern of nuclear staining (Fig. 1a). Many of the stimulated B cells also formed Nbs1 foci (32% contained, on average, 3 ± 2 per cell) and γ-H2AX foci (40% contained, on average, 4.5 ± 3 per cell). To determine which of these repair factors are co-localized in activated B cells, we performed two colour immunofluoresence experiments (Fig. 1b). Only 20% of the cells that contained Rad51 and Nbs1 (n = 687) or Brca1 and Nbs1 foci (n = 431) exhibited co-localization. In contrast, γ-H2AX foci co-localiz...

show abstract

Dynamic Changes of BRCA1 Subnuclear Location and Phosphorylation State Are Initiated by DNA Damage

Cited by 859 publications

References 52 publications

The plant‐specific CDKB 1‐ CYCB 1 complex mediates homologous recombination repair in Arabidopsis

The plant‐specific CDKB 1‐ CYCB 1 complex mediates homologous recombination repair in Arabidopsis

BRCA1 physically associates with p53 and stimulates its transcriptional activity

AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching

Contact Info

Product

Resources

About