BRCA1 Functions Independently of Homologous Recombination in DNA Interstrand Crosslink Repair

被引：217

作者：

Bunting, Samuel F. ^{[1
]}

Callen, Elsa ^{[1
]}

Kozak, Marina L. ^{[1
]}

Kim, Jung Min ^{[3
]}

Wong, Nancy ^{[1
]}

Lopez-Contreras, Andres J. ^{[4
]}

Ludwig, Thomas ^{[2
]}

Baer, Richard ^{[2
]}

Faryabi, Robert B. ^{[1
]}

Malhowski, Amy ^{[1
]}

Chen, Hua-Tang ^{[1
]}

Fernandez-Capetillo, Oscar ^{[4
]}

D'Andrea, Alan ^{[3
]}

Nussenzweig, Andre ^{[1
]}

机构：

[1] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA

[2] Columbia Univ, Med Ctr, Irving Canc Res Ctr, Inst Canc Genet, New York, NY 10032 USA

[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA

[4] Spanish Natl Canc Res Ctr, Genom Instabil Grp, Madrid, Spain

来源：

MOLECULAR CELL | 2012年 / 46卷 / 02期

关键词：

STRAND-BREAK REPAIR; CLASS-SWITCH RECOMBINATION; FANCONI-ANEMIA PATHWAY; V(D)J RECOMBINATION; DAMAGE-RESPONSE; CELL-CYCLE; POLY(ADP-RIBOSE) POLYMERASE; TUMOR SUPPRESSION; DEFICIENT CELLS; 53BP1;

D O I：

10.1016/j.molcel.2012.02.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：125 / 135

页数：11

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