PMID- 10395545
OWN - NLM
STAT- MEDLINE
DCOM- 19990917
LR  - 20211203
IS  - 0960-9822 (Print)
IS  - 0960-9822 (Linking)
VI  - 9
IP  - 13
DP  - 1999 Jul 1
TI  - Identification of a defect in DNA ligase IV in a radiosensitive leukaemia
      patient.
PG  - 699-702
AB  - The major mechanism for the repair of DNA double-strand breaks (DSBs) in
      mammalian cells is non-homologous end-joining (NHEJ), a process that involves the
      DNA-dependent protein kinase [1] [2], XRCC4 and DNA ligase IV [3] [4] [5] [6].
      Rodent cells and mice defective in these components are radiation-sensitive and
      defective in V(D)J-recombination, showing that NHEJ also functions to rejoin DSBs
      introduced during lymphocyte development [7] [8]. 180BR is a radiosensitive cell 
      line defective in DSB repair, which was derived from a leukaemia patient who was 
      highly sensitive to radiotherapy [9] [10] [11]. We have identified a mutation
      within a highly conserved motif encompassing the active site in DNA ligase IV
      from 180BR cells. The mutated protein is severely compromised in its ability to
      form a stable enzyme-adenylate complex, although residual activity can be
      detected at high ATP concentrations. Our results characterize the first patient
      with a defect in an NHEJ component and suggest that a significant defect in NHEJ 
      that leads to pronounced radiosensitivity is compatible with normal human
      viability and does not cause any major immune dysfunction. The defect, however,
      may confer a predisposition to leukaemia.
FAU - Riballo, E
AU  - Riballo E
AD  - MRC Cell Mutation Unit, University of Sussex, Brighton, BN1 9RR, UK.
FAU - Critchlow, S E
AU  - Critchlow SE
FAU - Teo, S H
AU  - Teo SH
FAU - Doherty, A J
AU  - Doherty AJ
FAU - Priestley, A
AU  - Priestley A
FAU - Broughton, B
AU  - Broughton B
FAU - Kysela, B
AU  - Kysela B
FAU - Beamish, H
AU  - Beamish H
FAU - Plowman, N
AU  - Plowman N
FAU - Arlett, C F
AU  - Arlett CF
FAU - Lehmann, A R
AU  - Lehmann AR
FAU - Jackson, S P
AU  - Jackson SP
FAU - Jeggo, P A
AU  - Jeggo PA
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Curr Biol
JT  - Current biology : CB
JID - 9107782
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (LIG4 protein, human)
RN  - 0 (Nuclear Proteins)
RN  - 0 (XRCC4 protein, human)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (PRKDC protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 6.5.1.- (DNA Ligases)
RN  - EC 6.5.1.1 (DNA Ligase ATP)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cell Line, Transformed
MH  - DNA Ligase ATP
MH  - DNA Ligases/*genetics/metabolism
MH  - *DNA Repair/genetics
MH  - DNA-Activated Protein Kinase
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Fibroblasts/radiation effects
MH  - Humans
MH  - Mutation
MH  - Nuclear Proteins
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics/radiotherapy
MH  - Protein Serine-Threonine Kinases/genetics/metabolism
MH  - Rabbits
MH  - Radiation Tolerance/*genetics
MH  - Radiation, Ionizing
MH  - Sequence Analysis, DNA
EDAT- 1999/07/08 00:00
MHDA- 1999/07/08 00:01
CRDT- 1999/07/08 00:00
PHST- 1999/07/08 00:00 [pubmed]
PHST- 1999/07/08 00:01 [medline]
PHST- 1999/07/08 00:00 [entrez]
AID - S0960-9822(99)80311-X [pii]
AID - 10.1016/s0960-9822(99)80311-x [doi]
PST - ppublish
SO  - Curr Biol. 1999 Jul 1;9(13):699-702. doi: 10.1016/s0960-9822(99)80311-x.