BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair

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

doi:10.1016/j.molcel.2012.02.015

BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair

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

194 Citationer (Scopus)

Abstract

Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage response factor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice and rescues HR deficiency, as measured by hypersensitivity to polyADP-ribose polymerase (PARP) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA crosslink repair that is distinct from HR. Disruption of the nonhomologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2 provides a key activity that cannot be bypassed by ablation of 53BP1 or Ku.

Originalsprog	Engelsk
Tidsskrift	Molecular Cell
Vol/bind	46
Udgave nummer	2
Sider (fra-til)	125-35
Antal sider	11
ISSN	1097-2765
DOI	https://doi.org/10.1016/j.molcel.2012.02.015
Status	Udgivet - 27 apr. 2012
Udgivet eksternt	Ja

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10.1016/j.molcel.2012.02.015

Citationsformater

Bunting, S. F., Callén, E., Kozak, M. L., Kim, J. M., Wong, N., López-Contreras, A. J., Ludwig, T., Baer, R., Faryabi, R. B., Malhowski, A., Chen, H.-T., Fernandez-Capetillo, O., D'Andrea, A., & Nussenzweig, A. (2012). BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Molecular Cell, 46(2), 125-35. https://doi.org/10.1016/j.molcel.2012.02.015

Bunting, SF, Callén, E, Kozak, ML, Kim, JM, Wong, N, López-Contreras, AJ, Ludwig, T, Baer, R, Faryabi, RB, Malhowski, A, Chen, H-T, Fernandez-Capetillo, O, D'Andrea, A & Nussenzweig, A 2012, 'BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair', Molecular Cell, bind 46, nr. 2, s. 125-35. https://doi.org/10.1016/j.molcel.2012.02.015

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title = "BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair",

abstract = "Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage response factor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice and rescues HR deficiency, as measured by hypersensitivity to polyADP-ribose polymerase (PARP) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA crosslink repair that is distinct from HR. Disruption of the nonhomologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2 provides a key activity that cannot be bypassed by ablation of 53BP1 or Ku.",

keywords = "Animals, Antigens, Nuclear, BRCA1 Protein, DNA Repair, DNA-Binding Proteins, Fanconi Anemia Complementation Group D2 Protein, Gene Knockdown Techniques, Genomic Instability, Homologous Recombination, Mice, Sequence Deletion",

author = "Bunting, {Samuel F} and Elsa Call{\'e}n and Kozak, {Marina L} and Kim, {Jung Min} and Nancy Wong and L{\'o}pez-Contreras, {Andr{\'e}s J} and Thomas Ludwig and Richard Baer and Faryabi, {Robert B} and Amy Malhowski and Hua-Tang Chen and Oscar Fernandez-Capetillo and Alan D'Andrea and Andr{\'e} Nussenzweig",

year = "2012",

month = apr,

day = "27",

doi = "10.1016/j.molcel.2012.02.015",

language = "English",

volume = "46",

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journal = "Molecular Cell",

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TY - JOUR

T1 - BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair

AU - Bunting, Samuel F

AU - Callén, Elsa

AU - Kozak, Marina L

AU - Kim, Jung Min

AU - Wong, Nancy

AU - López-Contreras, Andrés J

AU - Ludwig, Thomas

AU - Baer, Richard

AU - Faryabi, Robert B

AU - Malhowski, Amy

AU - Chen, Hua-Tang

AU - Fernandez-Capetillo, Oscar

AU - D'Andrea, Alan

AU - Nussenzweig, André

PY - 2012/4/27

Y1 - 2012/4/27

N2 - Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage response factor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice and rescues HR deficiency, as measured by hypersensitivity to polyADP-ribose polymerase (PARP) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA crosslink repair that is distinct from HR. Disruption of the nonhomologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2 provides a key activity that cannot be bypassed by ablation of 53BP1 or Ku.

AB - Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage response factor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice and rescues HR deficiency, as measured by hypersensitivity to polyADP-ribose polymerase (PARP) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA crosslink repair that is distinct from HR. Disruption of the nonhomologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2 provides a key activity that cannot be bypassed by ablation of 53BP1 or Ku.

KW - Animals

KW - Antigens, Nuclear

KW - BRCA1 Protein

KW - DNA Repair

KW - DNA-Binding Proteins

KW - Fanconi Anemia Complementation Group D2 Protein

KW - Gene Knockdown Techniques

KW - Genomic Instability

KW - Homologous Recombination

KW - Mice

KW - Sequence Deletion

U2 - 10.1016/j.molcel.2012.02.015

DO - 10.1016/j.molcel.2012.02.015

M3 - Journal article

C2 - 22445484

SN - 1097-2765

VL - 46

SP - 125

EP - 135

JO - Molecular Cell

JF - Molecular Cell

IS - 2

ER -

BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair

Abstract

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