MDC1 is ubiquitylated on its tandem BRCT domain and directly binds RAP80 in a UBC13-dependent manner

Strauss, Carmit; Halevy, Tomer; Macarov, Michal; Argaman, Liron; Goldberg, Michal

doi:10.1016/j.dnarep.2011.04.016

Cited by 16 publications

(24 citation statements)

References 51 publications

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“…at Lys1977) via K63 of ubiquitin, a modification not influenced by DSB induction [398]. This modification appears to promote the direct interaction between a minor portion of MDC1 molecules and RAP80, and the functional significance of this interaction is supported by a RAP80 delE81 point mutation, identified in familial breast cancer, that blocks the interaction [398]. This damage-independent interaction is required for the damage-dependent recruitment of RAP80 into nuclear foci [399] discussed in the next section.…”

Section: Binding Of Mdc1 To Gh2ax Facilitates Recruitment Of Key Playersmentioning

confidence: 90%

“…Besides the role of RNF8 in MDC1-dependent BRCA1 localization into IR-induced foci, there appears to be an RNF8-independent component [398,554]. Knockdown experiments suggest a portion of the foci containing conjugated ubiquitin is RNF8-independent and MDC1-dependent [554].…”

Section: Contribution Of K48-ubiquitylation and Proteasome Processingmentioning

confidence: 90%

“…MDC1 is constitutively ubiquitylated on its BRCT domain (e.g. at Lys1977) via K63 of ubiquitin, a modification not influenced by DSB induction [398]. This modification appears to promote the direct interaction between a minor portion of MDC1 molecules and RAP80, and the functional significance of this interaction is supported by a RAP80 delE81 point mutation, identified in familial breast cancer, that blocks the interaction [398].…”

Section: Binding Of Mdc1 To Gh2ax Facilitates Recruitment Of Key Playersmentioning

confidence: 96%

“…Recent work suggests that regulatory ubiquitylation of MDC1 is an important event for the recruitment of the downstream protein RAP80 (receptor-associated protein 80) [398]. MDC1 is constitutively ubiquitylated on its BRCT domain (e.g.…”

Section: Binding Of Mdc1 To Gh2ax Facilitates Recruitment Of Key Playersmentioning

confidence: 99%

See 3 more Smart Citations

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

Thompson

2012

Mutation Research/Reviews in Mutation Research

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Section: Binding Of Mdc1 To Gh2ax Facilitates Recruitment Of Key Playersmentioning

confidence: 90%

Section: Contribution Of K48-ubiquitylation and Proteasome Processingmentioning

confidence: 90%

Section: Binding Of Mdc1 To Gh2ax Facilitates Recruitment Of Key Playersmentioning

confidence: 96%

Section: Binding Of Mdc1 To Gh2ax Facilitates Recruitment Of Key Playersmentioning

confidence: 99%

See 2 more Smart Citations

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

Thompson

2012

Mutation Research/Reviews in Mutation Research

323

283

View full text Add to dashboard Cite

“…So far, histones H2A and H2AX have been indicated as substrates of these E3 ligases although yet unidentified substrates at DSBs may also likely exist. A recent report indicates that MDC1 is likely to be another substrate with a lysine residue in the MDC BRCT domain ubiquitinated in a Ubc13-dependent manner for interaction and optimum recruitment of Rap80 [68]. Unlike the canonical Lys48-linked polyUb that targets the substrate protein for proteasomal degradation, RNF8/RNF168-dependent ubiquitination around DNA damage sites appears to generate K63-linked polyUb for recruitment of DNA repair proteins [3,[60][61][62][63][64].…”

mentioning

confidence: 99%

BRCA1 tumor suppressor network: focusing on its tail

Wang

2012

Cell & Bioscience

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Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer. BRCA1 plays critical roles in the DNA damage response that regulates activities of multiple repair and checkpoint pathways for maintaining genome stability. The BRCT domains of BRCA1 constitute a phospho-peptide binding domain recognizing a phospho-SPxF motif (S, serine; P, proline; × varies; F, phenylalanine). The BRCT domains are frequently targeted by clinically important mutations and most of these mutations disrupt the binding surface of the BRCT domains to phosphorylated peptides. The BRCT domain and its capability to bind phosphorylated protein is required for the tumor suppressor function of BRCA1. Through its BRCT phospho-binding ability BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP. The A, B and C complexes, at lease partially undertake BRCA1's role in mechanisms of cell cycle checkpoint and DNA repair that maintain genome stability, thus may play important roles in BRCA1's tumor suppressor function.Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer [1,2]. BRCA1 plays critical roles in a number of diverse cellular processes that ensure genome integrity and the increase risk of breast and ovarian cancer caused by mutation of BRCA1 has been attributed to increased genomic instability. To safeguard genome, cells have evolved a defensive mechanism, called the DNA damage response (DDR), to coordinate multiple cellular responses including DNA repair, cell cycle checkpoint regulation, transcription, senescence or apoptosis etc., to counteract genotoxic stress [3][4][5][6]. BRCA1 appears to act as a central mediator of the cellular response to DNA damage that regulates the activities of multiple repair and checkpoint pathways [3,5,[7][8][9][10]. BRCA1 is a substrate of the central DNA damage response kinases ATM/ATR that control the DDR. It is required for homology directed repair, a pathway that facilitates error-free repair of double-strand breaks (DSBs) and resolution of stalled DNA replication forks through homologous recombination (HR) [9][10][11] as well as postreplicative repair in response to UV damage [12]. Recently it is suggested that much of BRCA1's role in maintaining genome stability is accounted for by its role in maintaining heterochromatin integrity via H2A ubiquitination [13].BRCA1 associates with multiple repair proteins and cell cycle regulators and such a capability to form multiple protein complexes contributes to its role in maintaining chromosome stability and tumor suppression (Figure 1). BRCA1 is a large protein of 1,863 amino acids. It contains two important domains at each end of the protein, a RING domain at the N-terminus and two BRCT domains at the C-terminus. Many clinically important mutations of BRCA1 gene frequently target these two domains. BRCA1 dimerizes with BARD1 through the RING domain present on each or the protein, forming...

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Chk1 inhibitor synergizes quinacrine mediated apoptosis in breast cancer cells by compromising the base excision repair cascade

Preet

Siddharth

Satapathy

et al. 2016

Biochemical Pharmacology

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MDC1 is ubiquitylated on its tandem BRCT domain and directly binds RAP80 in a UBC13-dependent manner

Cited by 16 publications

References 51 publications

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

BRCA1 tumor suppressor network: focusing on its tail

Chk1 inhibitor synergizes quinacrine mediated apoptosis in breast cancer cells by compromising the base excision repair cascade

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