Ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases have overlapping activities during chromosomal signal joint formation.
Lymphocyte antigen receptor gene assembly occurs through the process of V(D)J recombination, which is initiated when the RAG endonuclease introduces DNA DSBs at two recombining gene segments to form broken DNA coding end pairs and signal end pairs. These paired DNA ends are joined by proteins of the nonhomologous end-joining (NHEJ) pathway of DSB repair to form a coding joint and signal joint, respectively. RAG DSBs are generated in G1-phase developing lymphocytes, where they activate the ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases to orchestrate diverse cellular DNA damage responses including DSB repair. Paradoxically, although Atm and DNA-PKcs both function during coding joint formation, Atm appears to be dispensible for signal joint formation; and although some studies have revealed an activity for DNA-PKcs during signal joint formation, others have not. Here we show that Atm and DNA-PKcs have overlapping catalytic activities that are required for chromosomal signal joint formation and for preventing the aberrant resolution of signal ends as potentially oncogenic chromosomal translocations.
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Eric J
EJ
Gapud
Yair
Y
Dorsett
Bu
B
Yin
Elsa
E
Callen
Andrea
A
Bredemeyer
Grace K
GK
Mahowald
Kazuo Q
KQ
Omi
Laura M
LM
Walker
Jeffrey J
JJ
Bednarski
Peter J
PJ
McKinnon
Craig H
CH
Bassing
Andre
A
Nussenzweig
Barry P
BP
Sleckman
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002875:Chromosomes; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D017346:Protein Serine-Threonine Kinases
Science. 2000 Dec 8;290(5498):1962-5
11110662
Mol Cell Biol. 2006 Feb;26(4):1558-68
16449665
Cell. 1988 Oct 7;55(1):7-16
3167977
Mol Cell. 2009 May 15;34(3):298-310
19450528
Annu Rev Immunol. 2000;18:495-527
10837067
Nature. 2011 Jan 13;469(7329):245-9
21160476
Immunol Rev. 2004 Aug;200:115-31
15242400
Mol Cell. 2009 May 15;34(3):285-97
19450527
J Biochem Mol Biol. 2007 May 31;40(3):432-8
17562296
J Immunol. 2000 Feb 1;164(3):1416-24
10640757
DNA Repair (Amst). 2005 Aug 15;4(9):1006-18
15941674
Biochem J. 2002 Nov 15;368(Pt 1):243-51
12186630
Genes Dev. 2006 Jun 15;20(12):1575-82
16778076
Mol Cell. 2008 Sep 5;31(5):631-40
18775323
Immunity. 1998 Sep;9(3):355-66
9768755
J Biol Chem. 2004 Sep 3;279(36):37282-90
15194694
Immunity. 1995 Jan;2(1):101-12
7600297
Science. 2007 May 25;316(5828):1160-6
17525332
J Cell Biol. 2007 Apr 23;177(2):219-29
17438073
J Exp Med. 2007 Oct 1;204(10):2293-303
17785508
Mol Cell Biol. 2007 May;27(10):3881-90
17353268
Genes Dev. 1995 Oct 1;9(19):2409-20
7557392
Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):12926-31
11606753
Cell Motil Cytoskeleton. 2008 Apr;65(4):281-94
18200567
Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18339-44
19820166
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3243-8
11248063
Curr Biol. 2001 Feb 6;11(3):191-4
11231155
Immunol Rev. 2006 Feb;209:142-58
16448540
DNA Repair (Amst). 2004 Mar 4;3(3):267-76
15177042
DNA Repair (Amst). 2004 Aug-Sep;3(8-9):817-26
15279766
J Exp Med. 2009 Mar 16;206(3):669-79
19221393
Genes Dev. 2009 Jan 15;23(2):171-80
19171781
Mol Cell. 2002 Apr;9(4):871-8
11983177
Nature. 2000 Nov 23;408(6811):433-9
11100718
DNA Repair (Amst). 2008 Oct 1;7(10):1680-92
18644470
Nature. 2006 Jul 27;442(7101):466-70
16799570
J Biol Chem. 2007 Mar 2;282(9):6582-7
17189255
EMBO Rep. 2009 Jun;10(6):629-35
19444312
J Immunol. 2000 Oct 1;165(7):3883-9
11034395
Immunity. 1998 Sep;9(3):367-76
9768756
Mol Cell Biol. 2005 Dec;25(24):10842-52
16314509
Nat Immunol. 2003 Jan;4(1):31-7
12469118
J Biol Chem. 1993 Sep 25;268(27):20105-9
8397200
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6323-8
17405860
Mol Immunol. 1999 Dec;36(18):1263-9
10684966
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15559-64
9861008