The Experts below are selected from a list of 13122 Experts worldwide ranked by ideXlab platform
Luca Pellegrini - One of the best experts on this subject based on the ideXlab platform.
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Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of BRCA2 and Stable Rad51 Nucleofilaments.
Molecular cell, 2017Co-Authors: Arun Mouli Kolinjivadi, Alberto Ciccia, Vincenzo Sannino, Anna De Antoni, Karina Zadorozhny, Mairi L. Kilkenny, Hervé Técher, G. Baldi, Rong Shen, Luca PellegriniAbstract:BRCA2 deficiency causes Mre11-dependent degradation of nascent DNA at stalled forks, leading to cell lethality. To understand the molecular mechanisms underlying this process, we isolated Xenopus laevis BRCA2. We demonstrated that BRCA2 Protein prevents single-stranded DNA gap accumulation at replication fork junctions and behind them by promoting Rad51 binding to replicating DNA. Without BRCA2, forks with persistent gaps are converted by Smarcal1 into reversed forks, triggering extensive Mre11-dependent nascent DNA degradation. Stable Rad51 nucleofilaments, but not RPA or Rad51T131P mutant Proteins, directly prevent Mre11-dependent DNA degradation. Mre11 inhibition instead promotes reversed fork accumulation in the absence of BRCA2. Rad51 directly interacts with the Pol α N-terminal domain, promoting Pol α and δ binding to stalled replication forks. This interaction likely promotes replication fork restart and gap avoidance. These results indicate that BRCA2 and Rad51 prevent formation of abnormal DNA replication intermediates, whose processing by Smarcal1 and Mre11 predisposes to genome instability.
Arun Mouli Kolinjivadi - One of the best experts on this subject based on the ideXlab platform.
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Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of BRCA2 and Stable Rad51 Nucleofilaments.
Molecular cell, 2017Co-Authors: Arun Mouli Kolinjivadi, Alberto Ciccia, Vincenzo Sannino, Anna De Antoni, Karina Zadorozhny, Mairi L. Kilkenny, Hervé Técher, G. Baldi, Rong Shen, Luca PellegriniAbstract:BRCA2 deficiency causes Mre11-dependent degradation of nascent DNA at stalled forks, leading to cell lethality. To understand the molecular mechanisms underlying this process, we isolated Xenopus laevis BRCA2. We demonstrated that BRCA2 Protein prevents single-stranded DNA gap accumulation at replication fork junctions and behind them by promoting Rad51 binding to replicating DNA. Without BRCA2, forks with persistent gaps are converted by Smarcal1 into reversed forks, triggering extensive Mre11-dependent nascent DNA degradation. Stable Rad51 nucleofilaments, but not RPA or Rad51T131P mutant Proteins, directly prevent Mre11-dependent DNA degradation. Mre11 inhibition instead promotes reversed fork accumulation in the absence of BRCA2. Rad51 directly interacts with the Pol α N-terminal domain, promoting Pol α and δ binding to stalled replication forks. This interaction likely promotes replication fork restart and gap avoidance. These results indicate that BRCA2 and Rad51 prevent formation of abnormal DNA replication intermediates, whose processing by Smarcal1 and Mre11 predisposes to genome instability.
Masayuki Takahashi - One of the best experts on this subject based on the ideXlab platform.
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design of potent inhibitors of human rad51 recombinase based on brc motifs of BRCA2 Protein modeling and experimental validation of a chimera peptide
Journal of Medicinal Chemistry, 2010Co-Authors: Julian Nomme, Axelle Renodoncorniere, Yuya Asanomi, Kazuyasu Sakaguchi, Alicja Z Stasiak, Andrzej Stasiak, Bengt Norden, Vinh Tran, Masayuki TakahashiAbstract:We have previously shown that a 28-amino acid peptide derived from the BRC4 motif of BRCA2 tumor suppressor inhibits selectively human RAD51 recombinase (HsRad51). With the aim of designing better inhibitors for cancer treatment, we combined an in silico docking approach with in vitro biochemical testing to construct a highly efficient chimera peptide from eight existing human BRC motifs. We built a molecular model of all BRC motifs complexed with HsRad51 based on the crystal structure of the BRC4 motif-HsRad51 complex, computed the interaction energy of each residue in each BRC motif, and selected the best amino acid residue at each binding position. This analysis enabled us to propose four amino acid substitutions in the BRC4 motif. Three of these increased the inhibitory effect in vitro, and this effect was found to be additive. We thus obtained a peptide that is about 10 times more efficient in inhibiting HsRad51-ssDNA complex formation than the original peptide.
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inhibition of filament formation of human rad51 Protein by a small peptide derived from the brc motif of the BRCA2 Protein
Genes to Cells, 2008Co-Authors: Julian Nomme, Axelle Renodoncorniere, Yoshimasa Takizawa, Susan F Martinez, Fabrice Fleury, Pierre Weigel, Ken Ichi Yamamoto, Hitoshi Kurumizaka, Masayuki TakahashiAbstract:Human Rad51 is a key element of recombinational DNA repair and is related to the resistance of cancer cells to chemo- and radiotherapies. The Protein is thus a potential target of anti-cancer treatment. The crystallographic analysis shows that the BRC-motif of the BRCA2 tumor suppressor is in contact with the subunit-subunit interface of Rad51 and could thus prevent filament formation of Rad51. However, biochemical analysis indicates that a BRC-motif peptide of 69 amino acids preferentially binds to the N-terminal part of Rad51. We show experimentally that a short peptide of 28 amino acids derived from the BRC4 motif binds to the subunit-subunit interface and dissociates its filament, both in the presence and absence of DNA, certainly by binding to dissociated monomers. The inhibition is efficient and specific for Rad51: the peptide does not even interact with Rad51 homologs or prevent their interaction with DNA. Neither the N-terminal nor the C-terminal half of the peptide interacts with human Rad51, indicating that both parts are involved in the interaction, as expected from the crystal structure. These results suggest the possibility of developing inhibitors of human Rad51 based on this peptide.
Rong Shen - One of the best experts on this subject based on the ideXlab platform.
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Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of BRCA2 and Stable Rad51 Nucleofilaments.
Molecular cell, 2017Co-Authors: Arun Mouli Kolinjivadi, Alberto Ciccia, Vincenzo Sannino, Anna De Antoni, Karina Zadorozhny, Mairi L. Kilkenny, Hervé Técher, G. Baldi, Rong Shen, Luca PellegriniAbstract:BRCA2 deficiency causes Mre11-dependent degradation of nascent DNA at stalled forks, leading to cell lethality. To understand the molecular mechanisms underlying this process, we isolated Xenopus laevis BRCA2. We demonstrated that BRCA2 Protein prevents single-stranded DNA gap accumulation at replication fork junctions and behind them by promoting Rad51 binding to replicating DNA. Without BRCA2, forks with persistent gaps are converted by Smarcal1 into reversed forks, triggering extensive Mre11-dependent nascent DNA degradation. Stable Rad51 nucleofilaments, but not RPA or Rad51T131P mutant Proteins, directly prevent Mre11-dependent DNA degradation. Mre11 inhibition instead promotes reversed fork accumulation in the absence of BRCA2. Rad51 directly interacts with the Pol α N-terminal domain, promoting Pol α and δ binding to stalled replication forks. This interaction likely promotes replication fork restart and gap avoidance. These results indicate that BRCA2 and Rad51 prevent formation of abnormal DNA replication intermediates, whose processing by Smarcal1 and Mre11 predisposes to genome instability.
G. Baldi - One of the best experts on this subject based on the ideXlab platform.
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Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of BRCA2 and Stable Rad51 Nucleofilaments.
Molecular cell, 2017Co-Authors: Arun Mouli Kolinjivadi, Alberto Ciccia, Vincenzo Sannino, Anna De Antoni, Karina Zadorozhny, Mairi L. Kilkenny, Hervé Técher, G. Baldi, Rong Shen, Luca PellegriniAbstract:BRCA2 deficiency causes Mre11-dependent degradation of nascent DNA at stalled forks, leading to cell lethality. To understand the molecular mechanisms underlying this process, we isolated Xenopus laevis BRCA2. We demonstrated that BRCA2 Protein prevents single-stranded DNA gap accumulation at replication fork junctions and behind them by promoting Rad51 binding to replicating DNA. Without BRCA2, forks with persistent gaps are converted by Smarcal1 into reversed forks, triggering extensive Mre11-dependent nascent DNA degradation. Stable Rad51 nucleofilaments, but not RPA or Rad51T131P mutant Proteins, directly prevent Mre11-dependent DNA degradation. Mre11 inhibition instead promotes reversed fork accumulation in the absence of BRCA2. Rad51 directly interacts with the Pol α N-terminal domain, promoting Pol α and δ binding to stalled replication forks. This interaction likely promotes replication fork restart and gap avoidance. These results indicate that BRCA2 and Rad51 prevent formation of abnormal DNA replication intermediates, whose processing by Smarcal1 and Mre11 predisposes to genome instability.