53BP1 fosters fidelity of homology-directed DNA repair
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
53BP1 fosters fidelity of homology-directed DNA repair. / Ochs, Fena; Somyajit, Kumar; Altmeyer, Matthias; Rask, Maj-Britt Druedahl; Lukas, Jiri; Lukas, Claudia.
In: Nature Structural and Molecular Biology, Vol. 23, No. 8, 08.2016, p. 714-21.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - 53BP1 fosters fidelity of homology-directed DNA repair
AU - Ochs, Fena
AU - Somyajit, Kumar
AU - Altmeyer, Matthias
AU - Rask, Maj-Britt Druedahl
AU - Lukas, Jiri
AU - Lukas, Claudia
PY - 2016/8
Y1 - 2016/8
N2 - Repair of DNA double-strand breaks (DSBs) in mammals is coordinated by the ubiquitin-dependent accumulation of 53BP1 at DSB-flanking chromatin. Owing to its ability to limit DNA-end processing, 53BP1 is thought to promote nonhomologous end-joining (NHEJ) and to suppress homology-directed repair (HDR). Here, we show that silencing 53BP1 or exhausting its capacity to bind damaged chromatin changes limited DSB resection to hyper-resection and results in a switch from error-free gene conversion by RAD51 to mutagenic single-strand annealing by RAD52. Thus, rather than suppressing HDR, 53BP1 fosters its fidelity. These findings illuminate causes and consequences of synthetic viability acquired through 53BP1 silencing in cells lacking the BRCA1 tumor suppressor. We show that such cells survive DSB assaults at the cost of increasing reliance on RAD52-mediated HDR, which may fuel genome instability. However, our findings suggest that when challenged by DSBs, BRCA1- and 53BP1-deficient cells may become hypersensitive to, and be eliminated by, RAD52 inhibition.
AB - Repair of DNA double-strand breaks (DSBs) in mammals is coordinated by the ubiquitin-dependent accumulation of 53BP1 at DSB-flanking chromatin. Owing to its ability to limit DNA-end processing, 53BP1 is thought to promote nonhomologous end-joining (NHEJ) and to suppress homology-directed repair (HDR). Here, we show that silencing 53BP1 or exhausting its capacity to bind damaged chromatin changes limited DSB resection to hyper-resection and results in a switch from error-free gene conversion by RAD51 to mutagenic single-strand annealing by RAD52. Thus, rather than suppressing HDR, 53BP1 fosters its fidelity. These findings illuminate causes and consequences of synthetic viability acquired through 53BP1 silencing in cells lacking the BRCA1 tumor suppressor. We show that such cells survive DSB assaults at the cost of increasing reliance on RAD52-mediated HDR, which may fuel genome instability. However, our findings suggest that when challenged by DSBs, BRCA1- and 53BP1-deficient cells may become hypersensitive to, and be eliminated by, RAD52 inhibition.
KW - Journal Article
U2 - 10.1038/nsmb.3251
DO - 10.1038/nsmb.3251
M3 - Journal article
C2 - 27348077
VL - 23
SP - 714
EP - 721
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
IS - 8
ER -
ID: 165179810