The Tandem BRCT Domain of 53BP1 Is Not Required for Its Repair Function*

53BP1 plays an important role in cellular response to DNA damage. It is thought to be the mammalian homologue of budding yeast Rad9 and/or fission yeast Crb2. Rad9/Crb2 are bona fide checkpoint proteins whose activation requires their corresponding C-terminal tandem BRCT (BRCA1 C-terminal) motifs, which mediate their oligomerization and phosphorylation at multiple sites following DNA damage. Here we show that the function of human 53BP1 similarly depends on its oligomerization and phosphorylation at multiple sites but in a BRCT domain-independent manner. Moreover, unlike its proposed yeast counterparts, human 53BP1 only has limited checkpoint functions but rather acts as an adaptor in the repair of DNA double strand breaks. This difference in function may reflect the higher complexity of the DNA damage response network in metazoa including the evolution of other BRCT domain-containing proteins that may have functions redundant or overlapping with those of 53BP1.

[1]  J. Lieberman,et al.  A phosphatase complex that dephosphorylates γH2AX regulates DNA damage checkpoint recovery , 2006, Nature.

[2]  J. Lieberman,et al.  γ-H2AX Dephosphorylation by Protein Phosphatase 2A Facilitates DNA Double-Strand Break Repair , 2005 .

[3]  S. Elledge,et al.  53BP1 Oligomerization is Independent of its Methylation by PRMT1 , 2005, Cell cycle.

[4]  T. Ried,et al.  53BP1 Cooperates with p53 and Functions as a Haploinsufficient Tumor Suppressor in Mice , 2005, Molecular and Cellular Biology.

[5]  D. Durocher,et al.  Saccharomyces cerevisiae Rad9 Acts as a Mec1 Adaptor to Allow Rad53 Activation , 2005, Current Biology.

[6]  S. Bekker-Jensen,et al.  Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1 , 2005, The Journal of cell biology.

[7]  Martin Kühne,et al.  A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. , 2004, Molecular cell.

[8]  J. Mata,et al.  Methylation of Histone H4 Lysine 20 Controls Recruitment of Crb2 to Sites of DNA Damage , 2004, Cell.

[9]  Tom J. Petty,et al.  Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks , 2004, Nature.

[10]  P. Russell,et al.  Homo-oligomerization Is the Essential Function of the Tandem BRCT Domains in the Checkpoint Protein Crb2* , 2004, Journal of Biological Chemistry.

[11]  M. Nussenzweig,et al.  53BP1 is required for class switch recombination , 2004, The Journal of cell biology.

[12]  F. Alt,et al.  53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination , 2004, Nature Immunology.

[13]  Kai Rothkamm,et al.  A Double-Strand Break Repair Defect in ATM-Deficient Cells Contributes to Radiosensitivity , 2004, Cancer Research.

[14]  Michael B Yaffe,et al.  BRCT Repeats As Phosphopeptide-Binding Modules Involved in Protein Targeting , 2003, Science.

[15]  Georges Mer,et al.  The BRCT Domain Is a Phospho-Protein Binding Domain , 2003, Science.

[16]  P. Jeggo,et al.  Potential Role for 53BP1 in DNA End-joining Repair through Direct Interaction with DNA* , 2003, Journal of Biological Chemistry.

[17]  R. Bonner,et al.  Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks , 2003, Nature Cell Biology.

[18]  Junjie Chen,et al.  Accumulation of Checkpoint Protein 53BP1 at DNA Breaks Involves Its Binding to Phosphorylated Histone H2AX* , 2003, Journal of Biological Chemistry.

[19]  Junjie Chen,et al.  p53 Binding Protein 53BP1 Is Required for DNA Damage Responses and Tumor Suppression in Mice , 2003, Molecular and Cellular Biology.

[20]  Jiri Bartek,et al.  53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer , 2002, Nature Cell Biology.

[21]  A. Nussenzweig,et al.  DNA damage-induced G2–M checkpoint activation by histone H2AX and 53BP1 , 2002, Nature Cell Biology.

[22]  S. Elledge,et al.  53BP1, a Mediator of the DNA Damage Checkpoint , 2002, Science.

[23]  Thomas Ried,et al.  Evidence for Replicative Repair of DNA Double-Strand Breaks Leading to Oncogenic Translocation and Gene Amplification , 2002, The Journal of experimental medicine.

[24]  L. Serpell,et al.  Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor , 2002, The EMBO journal.

[25]  F. Alt,et al.  Unrepaired DNA Breaks in p53-Deficient Cells Lead to Oncogenic Gene Amplification Subsequent to Translocations , 2002, Cell.

[26]  D. Stern,et al.  Rad9 phosphorylation sites couple Rad53 to the Saccharomyces cerevisiae DNA damage checkpoint. , 2002, Molecular cell.

[27]  D. Livingston,et al.  Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure. , 2002, Genes & development.

[28]  C. Gilbert,et al.  Budding yeast Rad9 is an ATP-dependent Rad53 activating machine. , 2001, Molecular cell.

[29]  Junjie Chen,et al.  Tumor Suppressor P53 Binding Protein 1 (53bp1) Is Involved in DNA Damage–Signaling Pathways , 2001, The Journal of cell biology.

[30]  Y. Adachi,et al.  Phosphorylation and Rapid Relocalization of 53BP1 to Nuclear Foci upon DNA Damage , 2001, Molecular and Cellular Biology.

[31]  J. Morales,et al.  Negative Cell Cycle Regulation and DNA Damage-inducible Phosphorylation of the BRCT Protein 53BP1* , 2001, The Journal of Biological Chemistry.

[32]  T. Halazonetis,et al.  P53 Binding Protein 1 (53bp1) Is an Early Participant in the Cellular Response to DNA Double-Strand Breaks , 2000, The Journal of cell biology.

[33]  E. Rogakou,et al.  Megabase Chromatin Domains Involved in DNA Double-Strand Breaks in Vivo , 1999, The Journal of cell biology.

[34]  J. Soulier,et al.  The BRCT domain of the S. cerevisiae checkpoint protein Rad9 mediates a Rad9–Rad9 interaction after DNA damage , 1999, Current Biology.

[35]  Bin Li,et al.  Stimulation of p53-mediated Transcriptional Activation by the p53-binding Proteins, 53BP1 and 53BP2* , 1998, The Journal of Biological Chemistry.

[36]  M. Yanagida,et al.  Damage and replication checkpoint control in fission yeast is ensured by interactions of Crb2, a protein with BRCT motif, with Cut5 and Chk1. , 1997, Genes & development.

[37]  J. Mornon,et al.  From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair , 1997, FEBS letters.

[38]  Peer Bork,et al.  A superfamily of conserved domains in DNA damage‐ responsive cell cycle checkpoint proteins , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  S. Fields,et al.  Two cellular proteins that bind to wild-type but not mutant p53. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[40]  L. Hartwell,et al.  The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. , 1988, Science.