Second BRCT domain on Nijmegen syndrome breakage protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1949642893 135 ERKQIFKGKTFVFLNAKQHKKLSSAVVFGGGEARL-------------ITEENEEEESFFSAPGTCVVDIGITntqiiiT 201
Cdd:pfam16508   2 ERKTLFEGKTFVFLDQKQFERLSPPITNGGGKALLyevepgettpddfVRYVKNVGSELLTGKGVVVVRFRPK------K 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1949642893 202 DSQKKWVHLVMDVLQRH-GLRPIPEAEIGLAVIFMTTENYCNP 243
Cdd:pfam16508  76 SSNEEWIASFENELALRlGQRVIEQSEFLDAILHCSASKLCNP 118

forkhead associated (FHA) domain superfamily; Forkhead-associated (FHA) domains are small phosphopeptide recognition modules mostly found in eubacteria and eukaryotes. It is about 95-120 residues long that fold into an 11-stranded beta-sandwich. FHA domains can mediate the recognition of phosphorylated and non-phosphorylated substrates, as well as protein oligomerization. They specifically recognize threonine phosphorylation (pThr) accompanying activation of protein serine/threonine kinases. FHA domains show diverse ligand specificity. They may recognize the pTXXD motif, the pTXXI/L motif, and TQ clusters (singly and multiply phosphorylated). In eukaryotes, FHA superfamily members include forkhead-type transcription factors, as well as other signaling proteins, such as many regulatory proteins, kinases, phosphatases, motor proteins called kinesins, and metabolic enzymes. Many of them localize to the nucleus, where they participate in establishing or maintaining cell cycle checkpoints, DNA repair, or transcriptional regulation. FHA domains play important roles in human diseases, particularly in relation to DNA damage responses and cancers. In bacteria, FHA domain-containing proteins may participate in injection of viral proteins into host cells, transmembrane transporters, and cell division. FHA domain-containing proteins rarely include more than one copy of the domain. The only exception in eukaryotes is the checkpoint kinase Rad53 from Saccharomyces cerevisiae, which harbors two FHA domains (FHA1 and FHA2) flanking a central kinase domain. The two FHA domains recognize different phosphorylated targets and function independently from one another. In contrast, Mycobacterium tuberculosis ABC transporter Rv1747 contains two FHA domains but only one of them is essential for protein function.

                          10        20
                  ....*....|....*....|....*...
gi 1949642893   1 MQNGLPCTLKTGDRVTFGVFESKFRVEY 28
Cdd:cd22667    81 LKGGSEVTLKDGDVITFGVLGSKFRVEY 108

Second BRCT domain on Nijmegen syndrome breakage protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1949642893 135 ERKQIFKGKTFVFLNAKQHKKLSSAVVFGGGEARL-------------ITEENEEEESFFSAPGTCVVDIGITntqiiiT 201
Cdd:pfam16508   2 ERKTLFEGKTFVFLDQKQFERLSPPITNGGGKALLyevepgettpddfVRYVKNVGSELLTGKGVVVVRFRPK------K 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1949642893 202 DSQKKWVHLVMDVLQRH-GLRPIPEAEIGLAVIFMTTENYCNP 243
Cdd:pfam16508  76 SSNEEWIASFENELALRlGQRVIEQSEFLDAILHCSASKLCNP 118

forkhead associated (FHA) domain found in nibrin and similar proteins; Nibrin (NBN), also called cell cycle regulatory protein p95, or Nijmegen breakage syndrome protein 1 (NBS1), is a novel DNA double-strand break repair protein that is mutated in Nijmegen breakage syndrome. It is a component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. Nibrin modulates the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. Nibrin also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. Nibrin is a major player in the control of intra-S-phase checkpoint. This subfamily also includes Schizosaccharomyces pombe DNA repair and telomere maintenance protein Nbs1 and Arabidopsis thaliana AtNbs1. SpNbs1 is an FHA domain-containing protein required for DNA damage repair and S-phase DNA damage checkpoint. It is involved in telomere length maintenance and maintenance of chromatin structure. AtNbs1 is a component of MRN complex. It also functions in the very early stages of meiosis. The FHA domain is a small phosphopeptide recognition module.

                          10        20
                  ....*....|....*....|....*...
gi 1949642893   1 MQNGLPCTLKTGDRVTFGVFESKFRVEY 28
Cdd:cd22667    81 LKGGSEVTLKDGDVITFGVLGSKFRVEY 108

Second BRCT domain on Nijmegen syndrome breakage protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1949642893 135 ERKQIFKGKTFVFLNAKQHKKLSSAVVFGGGEARL-------------ITEENEEEESFFSAPGTCVVDIGITntqiiiT 201
Cdd:pfam16508   2 ERKTLFEGKTFVFLDQKQFERLSPPITNGGGKALLyevepgettpddfVRYVKNVGSELLTGKGVVVVRFRPK------K 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1949642893 202 DSQKKWVHLVMDVLQRH-GLRPIPEAEIGLAVIFMTTENYCNP 243
Cdd:pfam16508  76 SSNEEWIASFENELALRlGQRVIEQSEFLDAILHCSASKLCNP 118

C-terminal domain of the breast cancer suppressor protein (BRCA1) and related domains; The BRCT (BRCA1 C-terminus) domain is found within many DNA damage repair and cell cycle checkpoint proteins. BRCT domains interact with each other forming homo/hetero BRCT multimers, but are also involved in BRCT-non-BRCT interactions and interactions within DNA strand breaks. BRCT tandem repeats bind to phosphopeptides; it has been shown that the repeats in human BRCA1 bind specifically to pS-X-X-F motifs, mediating the interaction between BRCA1 and the DNA helicase BACH1, or BRCA1 and CtIP, a transcriptional corepressor. It is assumed that BRCT repeats play similar roles in many signaling pathways associated with the response to DNA damage.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1949642893  31 LVVCSSCLDIPGKTDLNQAVLQLGGLTTNSWTEECTHLVMTSVKVTIKTICALICGCPVVKPEYF 95
Cdd:cd00027     1 LVICFSGLDDEEREELKKLIEALGGKVSESLSSKVTHLIAKSPSGEKYYLAALAWGIPIVSPEWL 65

seventh BRCT domain of DNA topoisomerase 2-binding protein 1; TopBP1, also termed DNA topoisomerase II-beta-binding protein 1, or DNA topoisomerase II-binding protein 1, functions in DNA replication and damage response. It binds double-stranded DNA breaks and nicks as well as single-stranded DNA. TopBP1 contains six copies of BRCT domain. The family corresponds to the seventh BRCT domain. The Trp-X-X-X-Cys/Ser signature motif of the BRCT family is missing in this group.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1949642893  36 SCLDIPGKTDLNQAVLQLGG--LTTNSWTEECTHLVMTSVKVTIKTICALICGCPVVKPEYFSEFLKA 101
Cdd:cd17738     7 SGFSEDEKKELISIIEKLGGkvLDSDEFDPKCTHLICGKPSRSEKFLAACAAGKWILHPSYIEASAKA 74

first BRCT domain of BRCA1-associated RING domain protein 1 (Bard1) and similar proteins; Bard1, also termed BARD-1, or RING-type E3 ubiquitin transferase BARD1, is a critical factor in BRCA1-mediated tumor suppression and may also serve as a target for tumorigenic lesions in some human cancers. It associates with BRCA1 (breast cancer-1) to form a heterodimeric BRCA1/BARD1 complex that is responsible for maintaining genomic stability through nuclear functions involving DNA damage signaling and repair, transcriptional regulation, and cell cycle control. The BRCA1/BARD1 complex catalyzes autoubiquitination of BRCA1 and trans ubiquitination of other protein substrates. Its E3 ligase activity is dramatically reduced in the presence of UBX domain protein 1 (UBXN1). BARD-1 contains an N-terminal C3HC4-type RING-HC finger that binds BRCA1, and a C-terminal region with three ankyrin repeats and tandem BRCT domains that bind CstF-50 (cleavage stimulation factor) to modulate mRNA processing and RNAP II stability in response to DNA damage. The family corresponds to the first BRCT domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1949642893  31 LVVCSSCLDIPGKTDLNQAVLQLGGLTTNSWTEECTHLVMTSVKV-----TIKTICALICGCPVVKPEYFSEFLKA 101
Cdd:cd17734     1 LVLLGSGLSSEQKKLLEKLAQLLKAKVVTEFSPEVTHVVVPADERgvcprTMKYLMGILAGKWIVSFEWVEACLKA 76

BRCA1 C Terminus (BRCT) domain; The BRCT domain is found predominantly in proteins involved in cell cycle checkpoint functions responsive to DNA damage. The BRCT domain of XRCC1 forms a homodimer in the crystal structure. This suggests that pairs of BRCT domains associate as homo- or heterodimers. BRCT domains are often found as tandem-repeat pairs. Structures of the BRCA1 BRCT domains revealed a basis for a widely utilized head-to-tail BRCT-BRCT oligomerization mode. This conserved tandem BRCT architecture facilitates formation of the canonical BRCT phospho-peptide interaction cleft at a groove between the BRCT domains. Disease associated missense and nonsense mutations in the BRCA1 BRCT domains disrupt peptide binding by directly occluding this peptide binding groove, or by disrupting key conserved BRCT core folding determinants.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1949642893  31 LVVCSSCLDIPGKTDLNQAVLQLGGLTTNSWTEECTHLVMtsVKVTIKTICALICGCPVVKPEYF 95
Cdd:pfam00533   9 KTFVITGLDGLERDELKELIEKLGGKVTDSLSKKTTHVIV--EARTKKYLKAKELGIPIVTEEWL 71

second BRCT domain of DNA topoisomerase 2-binding protein 1 (TopBP1) and similar proteins; TopBP1, also termed DNA topoisomerase II-beta-binding protein 1, or DNA topoisomerase II-binding protein 1, functions in DNA replication and damage response. It binds double-stranded DNA breaks and nicks as well as single-stranded DNA. TopBP1 contains six copies of BRCT domain. The family corresponds to the second BRCT domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1949642893  31 LVVCSSCLDIPGKTDLNQAVLQLGGLTTNSWTEECTHLVmTSVKVTIKTICALICGC-PVVKPEYFSEFLKA 101
Cdd:cd17731     6 LVICVTGFDSEERKEIQQLVEQNGGSYSPDLSKNCTHLI-AGSPSGQKYEFARKWNSiHIVTPEWLYDSIEA 76

second BRCT domain of Schizosaccharomyces pombe BRCT-containing protein 1 (BRC1) and similar proteins; Schizosaccharomyces pombe BRC1 is required for mitotic fidelity, specifically in the G2 phase of the cell cycle. It plays a role in chromatin organization. The family also includes Cryptococcus neoformans DNA ligase 4 (LIG4, also known as DNA ligase IV or polydeoxyribonucleotide synthase [ATP] 4), which is involved in dsDNA break repair, and plays a role in non-homologous integration (NHI) pathways where it is required in the final step of non-homologus end-joining. Members in this family contains six BRCT domains. This family corresponds to the second repeat.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1949642893  31 LVVCSSCLDIPGKTDLNQAVLQLGGLTTNSWTEECTHLV---MTSVKVTIKTICALIcGCPVVKPEYFSEFLK 100
Cdd:cd18436     4 VVITCSDLPSGDKEAIYGGVLALGGQYSDELTRDVTHLIalsPDGDKYKTALKRPEL-NIKIVLPHWFDDCFK 75