BRCA1 Accelerates CtIP-Mediated DNA-End Resection

Cruz-García, Andrés; López-Saavedra, Ana; Huertas, Pablo

doi:10.1016/j.celrep.2014.08.076

Cited by 218 publications

(213 citation statements)

References 35 publications

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“…7,8,[37][38][39] BRCA1 tBRCT domain is responsible for promoting protein-protein interactions, mediating the recruitment and retention at the DSB sites. 35,36 During the DNA repair signaling, as DDR-related proteins are recruited to DSB sites, they accumulate and can be visualized as nuclear foci.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8] During the HR pathway BRCA1 is recruited to the DSB sites conducting repair through different complexes. 29 Taking into account CDK9 co-localization with BRCA1 at DNA damaged sites, we decided to investigate the role of CDK9 on BRCA1 IRIF formation using confocal microscopy (Fig.…”

Section: Cdk9 Modulates Brca1 Recruitment To Dsbsmentioning

confidence: 99%

“…[5][6][7] BRCA1 interacts with CtIP, stimulating the 5 0 end resection and as consequence the HR. 7,8 BRCA1-deficient cells present reduced HR repair efficiency that can lead to generate synthetic lethality toward PARP inhibitors, which is actually been used in anticancer therapeutic strategies. 9,10 BRCA1 acts commonly associated with BARD1 (BRCA1-associated RING domain protein 1) through dimerization of their RING-finger domains.…”

Section: Introductionmentioning

confidence: 99%

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BRCA1 recruitment to damaged DNA sites is dependent on CDK9

et al. 2017

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Double strand break lesions, the most toxic type of DNA damage, are repaired primarily through 2 distinct pathways: homology-directed recombination (HR) and non-homologous end-joining (NHEJ). BRCA1 and 53BP1, 2 proteins containing the BRCT modular domain, play an important role in DNA damage response (DDR) by orchestrating the decision between HR and NHEJ, but the precise mechanisms regarding both pathways are not entirely understood. Previously, our group identified a putative interaction between BRCA1 and BARD1 (BRCA1-associated RING domain 1) and the cyclin-dependent kinase (CDK9). CDK9 is a component of the positive transcription elongation complex and has been implicated in genome integrity maintenance associated with the replication stress response. Here we show that CDK9 interacts with endogenous BRCA1 and BARD1 mediated by their RING finger and BRCT domains, and describe CDK9 ionizing radiation-induced foci (IRIF) formation and its co-localization with BRCA1 in DNA damage sites. Cells lacking CDK9 are characterized by an altered g¡H2AX foci dynamics after DNA damage, a reduced efficiency in HR but not in NHEJ repair, failure to form BRCA1 and RAD51 IRIF and increased sensitivity to genotoxic agents. These data indicate that CDK9 is a player in the DDR and is consistent with its participation in HR pathway by modulating BRCA1 response.

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Section: Discussionmentioning

confidence: 99%

Section: Cdk9 Modulates Brca1 Recruitment To Dsbsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BRCA1 recruitment to damaged DNA sites is dependent on CDK9

et al. 2017

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“…In S/G2 phases, BRCA1 is recruited to DSBs, along with CtBP-interacting protein (CtIP) and the MRE11/ RAD50/NBS1 (MRN) complex, to facilitate the optimal initiation of DNA end resection (reviewed in Lamarche et al (2010) ; Fig. 3); however, the contribution of BRCA1 in promoting DNA end resection is not completely understood (Nakamura et al 2010, Reczek et al 2013, Cruz-Garcia et al 2014, Polato et al 2014. Extensive resection is subsequently carried out by the DNA replication ATP-dependent helicase-like homolog (DNA2), and the Exonuclease 1 (EXO1), with the help of the Bloom syndrome helicase (BLM) (Gravel et al 2008, Huertas et al 2008, Mimitou & Symington 2008, Nimonkar et al 2008, Zhu et al 2008, Cejka et al 2010, Niu et al 2010, Shim et al 2010, Garcia et al 2011.…”

Section: Brca2 Is a Central Mediator Of Dsb Repair By Hrmentioning

confidence: 99%

BRCA2 functions: from DNA repair to replication fork stabilization

Fradet-Turcotte¹,

Sitz²,

Grapton³

et al. 2016

Endocrine-Related Cancer

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Maintaining genomic integrity is essential to preserve normal cellular physiology and to prevent the emergence of several human pathologies including cancer. The breast cancer susceptibility gene 2 (BRCA2, also known as the Fanconi anemia (FA) complementation group D1 (FANCD1)) is a potent tumor suppressor that has been extensively studied in DNA double-stranded break (DSB) repair by homologous recombination (HR). However, BRCA2 participates in numerous other processes central to maintaining genome stability, including DNA replication, telomere homeostasis and cell cycle progression. Consequently, inherited mutations in BRCA2 are associated with an increased risk of breast, ovarian and pancreatic cancers. Furthermore, bi-allelic mutations in BRCA2 are linked to FA, a rare chromosome instability syndrome characterized by aplastic anemia in children as well as susceptibility to leukemia and cancer. Here, we discuss the recent developments underlying the functions of BRCA2 in the maintenance of genomic integrity. The current model places BRCA2 as a central regulator of genome stability by repairing DSBs and limiting replication stress. These findings have direct implications for the development of novel anticancer therapeutic approaches.

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“…CtIP plays a particularly important role in regulating resection, which is mediated through its interaction with BRCA1 [3]. In the following cascade of events, BRCA1 interacts directly with the BRCA2-PALB2 complex, which in turn is recruited to the ssDNA where it acts as a chaperone that stimulates the formation of RAD51 nucleoprotein filaments that drive homology-directed HR repair to restore the integrity of the DNA [4,5].…”

mentioning

confidence: 99%