scholarly journals RNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qian Zhu ◽  
Jinzhou Huang ◽  
Hongyang Huang ◽  
Huan Li ◽  
Peiqiang Yi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cell ◽  
Nuclear Export ◽  
Molecular Mechanisms ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Polymerase Inhibitors

AbstractBRCA1-BARD1 heterodimers act in multiple steps during homologous recombination (HR) to ensure the prompt repair of DNA double strand breaks. Dysfunction of the BRCA1 pathway enhances the therapeutic efficiency of poly-(ADP-ribose) polymerase inhibitors (PARPi) in cancers, but the molecular mechanisms underlying this sensitization to PARPi are not fully understood. Here, we show that cancer cell sensitivity to PARPi is promoted by the ring between ring fingers (RBR) protein RNF19A. We demonstrate that RNF19A suppresses HR by ubiquitinating BARD1, which leads to dissociation of BRCA1-BARD1 complex and exposure of a nuclear export sequence in BARD1 that is otherwise masked by BRCA1, resulting in the export of BARD1 to the cytoplasm. We provide evidence that high RNF19A expression in breast cancer compromises HR and increases sensitivity to PARPi. We propose that RNF19A modulates the cancer cell response to PARPi by negatively regulating the BRCA1-BARD1 complex and inhibiting HR-mediated DNA repair.

scholarly journals End-resection at DNA double-strand breaks in the three domains of life

2013 ◽  
Vol 41 (1) ◽  
pp. 314-320 ◽  
Author(s):  
John K. Blackwood ◽  
Neil J. Rzechorzek ◽  
Sian M. Bray ◽  
Joseph D. Maman ◽  
Luca Pellegrini ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Homologous Chromosomes ◽  
Domains Of Life ◽  
Strand Invasion ◽  
End Resection

During DNA repair by HR (homologous recombination), the ends of a DNA DSB (double-strand break) must be resected to generate single-stranded tails, which are required for strand invasion and exchange with homologous chromosomes. This 5′–3′ end-resection of the DNA duplex is an essential process, conserved across all three domains of life: the bacteria, eukaryota and archaea. In the present review, we examine the numerous and redundant helicase and nuclease systems that function as the enzymatic analogues for this crucial process in the three major phylogenetic divisions.

Synthetic lethality: exploiting the addiction of cancer to DNA repair

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6074-6082 ◽  
Author(s):  
Montaser Shaheen ◽  
Christopher Allen ◽  
Jac A. Nickoloff ◽  
Robert Hromas
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Synthetic Lethality ◽  
Double Strand Breaks ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Repair Pathways ◽  
Cancer Multiple

Abstract Because cancer at its origin must acquire permanent genomic mutations, it is by definition a disease of DNA repair. Yet for cancer cells to replicate their DNA and divide, which is the fundamental phenotype of cancer, multiple DNA repair pathways are required. This produces a paradox for the cancer cell, where its origin is at the same time its weakness. To overcome this difficulty, a cancer cell often becomes addicted to DNA repair pathways other than the one that led to its initial mutability. The best example of this is in breast or ovarian cancers with mutated BRCA1 or 2, essential components of a repair pathway for repairing DNA double-strand breaks. Because replicating DNA requires repair of DNA double-strand breaks, these cancers have become reliant on another DNA repair component, PARP1, for replication fork progression. The inhibition of PARP1 in these cells results in catastrophic double-strand breaks during replication, and ultimately cell death. The exploitation of the addiction of cancer cells to a DNA repair pathway is based on synthetic lethality and has wide applicability to the treatment of many types of malignancies, including those of hematologic origin. There is a large number of novel compounds in clinical trials that use this mechanism for their antineoplastic activity, making synthetic lethality one of the most important new concepts in recent drug development.

scholarly journals Homologous Recombination Deficiencies and Hereditary Tumors

2021 ◽  
Vol 23 (1) ◽  
pp. 348
Author(s):  
Hideki Yamamoto ◽  
Akira Hirasawa
Keyword(s):  
Homologous Recombination ◽  
Molecular Mechanisms ◽  
Double Strand Breaks ◽  
Repair System ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Pathogenic Variants ◽  
Inherited Susceptibility ◽  
Hereditary Tumors ◽  
Brca1 Brca2

Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor.

scholarly journals A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination

2021 ◽  
Author(s):  
Sara Marie Ambjoern ◽  
Julien P Duxin ◽  
Emil PT Hertz ◽  
Isha Nasa ◽  
Joana Duro ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Double Strand Breaks ◽  
Parp Inhibition ◽  
Binding Motif ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Atr Kinases

Mutations in the tumour suppressor gene BRCA2 are associated with predisposition to breast and ovarian cancers. BRCA2 has a central role in maintaining genome integrity by facilitating the repair of toxic DNA double-strand breaks (DSBs) by homologous recombination (HR). BRCA2 acts by promoting RAD51 nucleoprotein filament formation on resected single-stranded DNA, but how BRCA2 activity is regulated during HR is not fully understood. Here, we delineate a pathway where ATM and ATR kinases phosphorylate a highly conserved region in BRCA2 in response to DSBs. These phosphorylations stimulate the binding of the protein phosphatase PP2A-B56 to BRCA2 through a conserved binding motif. We show that the phosphorylation-dependent formation of the BRCA2-PP2A-B56 complex is required for efficient RAD51 loading to sites of DNA damage and HR-mediated DNA repair. Moreover, we find that several cancer-associated mutations in BRCA2 deregulate the BRCA2-PP2A-B56 interaction and sensitize cells to PARP inhibition. Collectively, our work uncovers PP2A-B56 as a positive regulator of BRCA2 function in HR with clinical implications for BRCA2 and PP2A-B56 mutated cancers.

scholarly journals Increased sensitivity of subtelomeric regions to DNA double-strand breaks in a human cancer cell line

DNA Repair ◽  
2009 ◽  
Vol 8 (8) ◽  
pp. 886-900 ◽  
Author(s):  
Oliver Zschenker ◽  
Avanti Kulkarni ◽  
Douglas Miller ◽  
Gloria. E. Reynolds ◽  
Marine Granger-Locatelli ◽  
...  
Keyword(s):  
Cell Line ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Line ◽  
Double Strand Breaks ◽  
Human Cancer Cell ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Increased Sensitivity ◽  
Subtelomeric Regions

scholarly journals CTCF cooperates with CtIP to drive homologous recombination repair of double-strand breaks

2019 ◽  
Vol 47 (17) ◽  
pp. 9160-9179 ◽  
Author(s):  
Soon Young Hwang ◽  
Mi Ae Kang ◽  
Chul Joon Baik ◽  
Yejin Lee ◽  
Ngo Thanh Hang ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Critical Role ◽  
Control Point ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
C Terminus ◽  
Dna End Resection ◽  
End Resection

Abstract The pleiotropic CCCTC-binding factor (CTCF) plays a role in homologous recombination (HR) repair of DNA double-strand breaks (DSBs). However, the precise mechanistic role of CTCF in HR remains largely unclear. Here, we show that CTCF engages in DNA end resection, which is the initial, crucial step in HR, through its interactions with MRE11 and CtIP. Depletion of CTCF profoundly impairs HR and attenuates CtIP recruitment at DSBs. CTCF physically interacts with MRE11 and CtIP and promotes CtIP recruitment to sites of DNA damage. Subsequently, CTCF facilitates DNA end resection to allow HR, in conjunction with MRE11–CtIP. Notably, the zinc finger domain of CTCF binds to both MRE11 and CtIP and enables proficient CtIP recruitment, DNA end resection and HR. The N-terminus of CTCF is able to bind to only MRE11 and its C-terminus is incapable of binding to MRE11 and CtIP, thereby resulting in compromised CtIP recruitment, DSB resection and HR. Overall, this suggests an important function of CTCF in DNA end resection through the recruitment of CtIP at DSBs. Collectively, our findings identify a critical role of CTCF at the first control point in selecting the HR repair pathway.

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