Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 829-842 |
| Number of pages | 14 |
| Journal | Molecular Cell |
| Volume | 55 |
| Issue number | 6 |
| DOIs | |
| State | Published - Sep 18 2014 |
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Chromosomal Translocations in Human Cells Are Generated by Canonical Nonhomologous End-Joining. / Ghezraoui, Hind; Piganeau, Marion; Renouf, Benjamin; Renaud, Jean Baptiste; Sallmyr, Annahita; Ruis, Brian L; Oh, Sehyun; Tomkinson, Alan E.; Hendrickson, Eric A; Giovannangeli, Carine; Jasin, Maria; Brunet, Erika.
In: Molecular Cell, Vol. 55, No. 6, 18.09.2014, p. 829-842.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chromosomal Translocations in Human Cells Are Generated by Canonical Nonhomologous End-Joining
AU - Ghezraoui, Hind
AU - Piganeau, Marion
AU - Renouf, Benjamin
AU - Renaud, Jean Baptiste
AU - Sallmyr, Annahita
AU - Ruis, Brian L
AU - Oh, Sehyun
AU - Tomkinson, Alan E.
AU - Hendrickson, Eric A
AU - Giovannangeli, Carine
AU - Jasin, Maria
AU - Brunet, Erika
PY - 2014/9/18
Y1 - 2014/9/18
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84907976219&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2014.08.002
DO - 10.1016/j.molcel.2014.08.002
M3 - Article
C2 - 25201414
AN - SCOPUS:84907976219
VL - 55
SP - 829
EP - 842
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 6
ER -