Chromosomal Translocations in Human Cells Are Generated by Canonical Nonhomologous End-Joining

被引：259

作者：

Ghezraoui, Hind ^{[1
,2
,3
]}

Piganeau, Marion ^{[1
,2
,3
]}

Renouf, Benjamin ^{[1
,2
,3
]}

Renaud, Jean-Baptiste ^{[1
,2
,3
]}

Sallmyr, Annahita ^{[4
,5
]}

Ruis, Brian ^{[6
]}

Oh, Sehyun ^{[6
]}

Tomkinson, Alan E. ^{[4
,5
]}

Hendrickson, Eric A. ^{[6
]}

Giovannangeli, Carine ^{[1
,2
,3
]}

Jasin, Maria ^{[7
]}

Brunet, Erika ^{[1
,2
,3
]}

机构：

[1] Museum Natl Hist Nat, F-75005 Paris, France

[2] CNRS, UMR7196, F-75005 Paris, France

[3] INSERM, U1154, F-75005 Paris, France

[4] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA

[5] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA

[6] Univ Minnesota, Sch Med, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA

[7] Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA

来源：

MOLECULAR CELL | 2014年 / 55卷 / 06期

关键词：

DNA-LIGASE IV; STRAND BREAK REPAIR; HUMAN SOMATIC-CELLS; V(D)J RECOMBINATION; MAMMALIAN-CELLS; KINASE-ACTIVITY; ZINC-FINGER; REARRANGEMENTS; BREAKPOINTS; XRCC4;

D O I：

10.1016/j.molcel.2014.08.002

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：

Breakpoint junctions of the chromosomal translocations that occur in human cancers display hallmarks of nonhomologous end-joining (NHEJ). In mouse cells, translocations are suppressed by canonical NHEJ (c-NHEJ) components, which include DNA ligase IV (LIG4), and instead arise from alternative NHEJ (alt-NHEJ). Here we used designer nucleases (ZFNs, TALENs, and CRISPR/Cas9) to introduce DSBs on two chromosomes to study translocation joining mechanisms in human cells. Remarkably, translocations were altered in cells deficient for LIG4 or its interacting protein XRCC4. Translocation junctions had significantly longer deletions and more microhomology, indicative of alt-NHEJ. Thus, unlike mouse cells, translocations in human cells are generated by c-NHEJ. Human cancer translocations induced by paired Cas9 nicks also showed a dependence on c-NHEJ, despite having distinct joining characteristics. These results demonstrate an unexpected and striking species-specific difference for common genomic rearrangements associated with tumorigenesis.

引用

页码：829 / 842

页数：14

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