BRCA1 Functions Independently of Homologous Recombination in DNA Interstrand Crosslink Repair

Bunting, Samuel F.; Callén, Elsa; Kozak, Marina; Kim, Jung Min; Wong, Nancy; López-Contreras, Andrés J.; Ludwig, Thomas; Baer, Richard; Faryabi, Robert B.; Malhowski, Amy J.; Chen, Hua-Tang; Fernández-Capetillo, Óscar; D’Andrea, Alan D.; Nussenzweig, André

doi:10.1016/j.molcel.2012.02.015

Cited by 235 publications

(303 citation statements)

References 56 publications

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“…1 A and B) (6)(7)(8). Furthermore, Nussenzweig and coworkers recently showed that BRCA1 activity is important for resistance to DNA interstrand cross-links in a manner that is separable from its role in HR (9). One common feature of the lesions created by UV, CDDP, and MMC is that they all have the potential to block the progression of replicative DNA polymerases and activate the DNA damage tolerance (DDT) pathway in mammalian cells (10)(11)(12).…”

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confidence: 99%

BRCA1promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade

Tian

Sharma

Zou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Breast cancer gene 1 ( BRCA1 ) deficient cells not only are hypersensitive to double-strand breaks but also are hypersensitive to UV irradiation and other agents that cause replication blockade; however, the molecular mechanisms behind these latter sensitivities are largely unknown. Here, we report that BRCA1 promotes cell survival by directly regulating the DNA damage tolerance pathway in response to agents that create cross-links in DNA. We show that BRCA1 not only promotes efficient mono- and polyubiquitination of proliferating cell nuclear antigen (PCNA) by regulating the recruitment of replication protein A, Rad18, and helicase-like transcription factor to chromatin but also directly recruits translesion polymerases, such as Polymerase eta and Rev1, to the lesions through protein–protein interactions. Our data suggest that BRCA1 plays a critical role in promoting translesion DNA synthesis as well as DNA template switching.

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mentioning

confidence: 99%

BRCA1promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade

Tian

Sharma

Zou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Loss of 53BP1 can rescue the HR defect and lethality observed in either Brca1 Δ11/Δ11 or Brca1-null cells and mice (42)(43)(44)(45). Similarly, decreased expression of the P53 binding protein 1 (53BP1) was detected in triple negative breast cancers as well as human BRCA1 tumors (45).…”

Section: Loss Of 53bp1 Fails To Rescue the Hr Defect Caused By Palb2mentioning

confidence: 98%

Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer

Bowman-Colin

Xia

Bunting

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HR-DSBR) through physical interactions with BRCA1, BRCA2, and RAD51. To further understand the mechanisms underlying PALB2-mediated DNA repair and tumor suppression functions, we targeted Palb2 in the mouse. Palb2-deficient murine ES cells recapitulated DNA damage defects caused by PALB2 depletion in human cells, and germline deletion of Palb2 led to early embryonic lethality. Somatic deletion of Palb2 driven by K14-Cre led to mammary tumor formation with long latency. Codeletion of both Palb2 and Tumor protein 53 (Trp53) accelerated mammary tumor formation. Like BRCA1 and BRCA2 mutant breast cancers, these tumors were defective in RAD51 focus formation, reflecting a defect in Palb2 HR-DSBR function, a strongly suspected contributor to Brca1, Brca2, and Palb2 mammary tumor development. However, unlike the case of Brca1-mutant cells, Trp53bp1 deletion failed to rescue the genomic instability of Palb2-or Brca2-mutant primary lymphocytes. Therefore, Palb2-driven DNA damage control is, in part, distinct from that executed by Brca1 and more similar to that of Brca2. The mechanisms underlying Palb2 mammary tumor suppression functions can now be explored genetically in vivo.mouse model | familial breast cancer

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“…Consequently, in cells lacking BRCA1, resection is not upregulated in S phase and inappropriate NHEJ occurs at replication-associated DSBs, leading to gross chromosomal rearrangements. In mice, deletion of 53BP1 suppresses the embryonic lethality and prevents the chromosomal rearrangements seen in BRCA1 Ϫ/Ϫ animals, emphasizing the importance of BRCA1-dependent removal of 53BP1 to facilitate the transition from NHEJ to HR (22)(23)(24)(25).…”

Section: Regulation Of the Onset Of Resection By 53bp1 And Brca1mentioning

confidence: 99%

53BP1, BRCA1, and the Choice between Recombination and End Joining at DNA Double-Strand Breaks

2014

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When DNA double-strand breaks occur, the cell cycle stage has a major influence on the choice of the repair pathway employed. Specifically, nonhomologous end joining is the predominant mechanism used in the G 1 phase of the cell cycle, while homologous recombination becomes fully activated in S phase. Studies over the past 2 decades have revealed that the aberrant joining of replication-associated breaks leads to catastrophic genome rearrangements, revealing an important role of DNA break repair pathway choice in the preservation of genome integrity. 53BP1, first identified as a DNA damage checkpoint protein, and BRCA1, a well-known breast cancer tumor suppressor, are at the center of this choice. Research on how these proteins function at the DNA break site has advanced rapidly in the recent past. Here, we review what is known regarding how the repair pathway choice is made, including the mechanisms that govern the recruitment of each critical factor, and how the cell transitions from end joining in G 1 to homologous recombination in S/G 2 .

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BRCA1 Functions Independently of Homologous Recombination in DNA Interstrand Crosslink Repair

Cited by 235 publications

References 56 publications

BRCA1promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade

BRCA1promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade

Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer

53BP1, BRCA1, and the Choice between Recombination and End Joining at DNA Double-Strand Breaks

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