PMID- 25642960
OWN - NLM
STAT- MEDLINE
DCOM- 20150227
LR  - 20231213
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 518
IP  - 7538
DP  - 2015 Feb 12
TI  - Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination.
PG  - 254-7
LID - 10.1038/nature14157 [doi]
AB  - The alternative non-homologous end-joining (NHEJ) machinery facilitates several 
      genomic rearrangements, some of which can lead to cellular transformation. This 
      error-prone repair pathway is triggered upon telomere de-protection to promote 
      the formation of deleterious chromosome end-to-end fusions. Using next-generation 
      sequencing technology, here we show that repair by alternative NHEJ yields 
      non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional 
      telomeres. Investigating the enzymatic activity responsible for the random 
      insertions enabled us to identify polymerase theta (Poltheta; encoded by Polq in 
      mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition 
      suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal 
      translocations at non-telomeric loci. In addition, we found that loss of Polq in 
      mice results in increased rates of homology-directed repair, evident by 
      recombination of dysfunctional telomeres and accumulation of RAD51 at 
      double-stranded breaks. Lastly, we show that depletion of Poltheta has a synergistic 
      effect on cell survival in the absence of BRCA genes, suggesting that the 
      inhibition of this mutagenic polymerase represents a valid therapeutic avenue for 
      tumours carrying mutations in homology-directed repair genes.
FAU - Mateos-Gomez, Pedro A
AU  - Mateos-Gomez PA
AD  - Skirball Institute of Biomolecular Medicine, Department of Cell Biology, NYU 
      School of Medicine, New York, New York 10016, USA.
FAU - Gong, Fade
AU  - Gong F
AD  - Department of Molecular Biosciences, Institute for Cellular and Molecular 
      Biology, University of Texas at Austin. 2506 Speedway Stop A5000, Austin, Texas 
      78712, USA.
FAU - Nair, Nidhi
AU  - Nair N
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, California 92037, USA.
FAU - Miller, Kyle M
AU  - Miller KM
AD  - Department of Molecular Biosciences, Institute for Cellular and Molecular 
      Biology, University of Texas at Austin. 2506 Speedway Stop A5000, Austin, Texas 
      78712, USA.
FAU - Lazzerini-Denchi, Eros
AU  - Lazzerini-Denchi E
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, California 92037, USA.
FAU - Sfeir, Agnel
AU  - Sfeir A
AD  - Skirball Institute of Biomolecular Medicine, Department of Cell Biology, NYU 
      School of Medicine, New York, New York 10016, USA.
LA  - eng
SI  - BioProject/PRJNA269507
GR  - P30 CA016087/CA/NCI NIH HHS/United States
GR  - R01 AG038677/AG/NIA NIH HHS/United States
GR  - AG038677/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20150202
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - EC 2.4.2.30 (PARP1 protein, human)
RN  - EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 2.7.7.- (Rad51 Recombinase)
RN  - EC 2.7.7.7 (DNA-Directed DNA Polymerase)
SB  - IM
CIN - Nature. 2015 Feb 12;518(7538):174-6. PMID: 25642961
CIN - Nat Rev Clin Oncol. 2015 Mar;12(3):125. PMID: 25687907
MH  - Animals
MH  - Base Sequence
MH  - Cell Death/genetics
MH  - Cell Line
MH  - Chromosome Aberrations
MH  - Chromosomes, Mammalian/genetics/*metabolism
MH  - *DNA Breaks, Double-Stranded
MH  - *DNA End-Joining Repair
MH  - DNA-Directed DNA Polymerase/deficiency/*metabolism
MH  - Genes, BRCA1
MH  - Genes, BRCA2
MH  - HeLa Cells
MH  - Humans
MH  - Mice
MH  - Poly (ADP-Ribose) Polymerase-1
MH  - Poly(ADP-ribose) Polymerases/genetics/metabolism
MH  - Rad51 Recombinase/metabolism
MH  - *Recombination, Genetic/genetics
MH  - Recombinational DNA Repair/genetics
MH  - Telomere/*genetics/*metabolism
MH  - Translocation, Genetic/genetics
MH  - DNA Polymerase theta
PMC - PMC4718306
MID - NIHMS745421
EDAT- 2015/02/03 06:00
MHDA- 2015/02/28 06:00
PMCR- 2016/01/19
CRDT- 2015/02/03 06:00
PHST- 2014/07/28 00:00 [received]
PHST- 2014/12/16 00:00 [accepted]
PHST- 2015/02/03 06:00 [entrez]
PHST- 2015/02/03 06:00 [pubmed]
PHST- 2015/02/28 06:00 [medline]
PHST- 2016/01/19 00:00 [pmc-release]
AID - nature14157 [pii]
AID - 10.1038/nature14157 [doi]
PST - ppublish
SO  - Nature. 2015 Feb 12;518(7538):254-7. doi: 10.1038/nature14157. Epub 2015 Feb 2.