Wednesday, May 1, 2013

REMEMBER THE BRCA FAMILY IS NOT THE ONLY DNA REPAIR GENE FAMILY!


1.NBS gene:
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Nijmegen breakage syndrome
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Nijmegen breakage syndrome
Classification and external resources
OMIM 251260
DiseasesDB 32395
eMedicine derm/725
MeSH D049932
Nijmegen breakage syndrome (NBS), also known as Berlin breakage syndrome and Seemanova syndrome, is a rare autosomal recessive[1] congenital disorder causing chromosomal instability, probably as a result of a defect in the Double Holliday junction DNA repair mechanism.
NBS1 codes for a protein that has two major functions: (1) to stop the cell cycle in the S phase, when there are errors in the cell DNA (2) to interact with FANCD2 that can activate the BRCA1/BRCA2 pathway of DNA repair. This explains clearly that mutations in the NBS1 gene lead to higher levels of cancer (see Fanconi anemia, Cockayne syndrome...)
The name derives from the Dutch city Nijmegen where the condition was first described.[2]
Most people with NBS have West Slavic origins. The largest number of them live in Poland.
Mrs Seemanova MD after whom the name of the syndrome was given, currently works at Motol Hospital, Prague, Czech Republic, as a Professor of medical genetics.===============================================

2. BLM gene
Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.[1]
The Bloom syndrome gene product is related to the RecQ subset of DExH box-containing DNA helicases and has both DNA-stimulated ATPase and ATP-dependent DNA helicase activities. Mutations causing Bloom syndrome delete or alter helicase motifs and may disable the 3' → 5' helicase activity. The normal protein may act to suppress inappropriate homologous recombination.[2]

Interactions

Bloom syndrome protein has been shown to interact with CHEK1,[3] Replication protein A1,[4][5][6] Werner syndrome ATP-dependent helicase,[7] RAD51L3,[8] Ataxia telangiectasia mutated,[9][10] RAD51,[11] XRCC2,[8] Flap structure-specific endonuclease 1,[12] H2AFX,[3] TP53BP1,[3] FANCM,[13] P53,[3][14][15][16] TOP3A,[4][17][18][19] MLH1[9][18][20][21] and CHAF1A.[22]

TO UNDERSTAND THAT THE BLM GENE IS A DNA REPAIR GENE, YOU MUST REMEMBER WHAT A 'HELICASE' IS:

Helicase

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Structure of E. coli helicase RuvA
DNA helicase
Identifiers
EC number 3.6.4.12
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
RNA helicase
Identifiers
EC number 3.6.4.13
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Helicases are a class of enzymes vital to all living organisms. Their main function is to unpackage an organism's genes. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands (i.e., DNA, RNA, or RNA-DNA hybrid) using energy derived from ATP hydrolysis. There are many helicases resulting from the great variety of processes in which strand separation must be catalyzed. Approximately 1% of eukaryotic genes code for helicases.[1] In humans, 95 non-redundant helicases are coded for in the genome, 64 RNA helicases and 31 DNA helicases.[2] Many cellular processes, such as DNA replication, transcription, translation, recombination, DNA repair, and ribosome biogenesis involve the separation of nucleic acid strands that necessitates the use of helicases.
 KEEFE ET AL" Bloom syndrome occurs most frequently in the Ashkenazi Jewish population with patients almost exclusively homozygous for a frameshift mutation resulting from a 6 bp deletion/7 bp insertion at nucleotide 2,281 (BLMAsh). This mutation causes premature termination of the encoded gene product producing a truncated protein of 739 amino acids while the full length protein contains 1417 amino acids.
The mutated gene in Bloom syndrome, BLM, was localized to chromosome 15q26.1 and encodes a member of the RecQ family of DNA helicases. This family also contains several other genes that are associated with disease phenotypes including the Werner Syndrome protein (WRN) and the defective protein in Rothmund-Thomson syndrome (RecQL4). Both of these diseases also feature an increased incidence of cancer. BLM, along with the rest of the members of this family, exhibits 3'-5' helicase activity and plays a role in DNA repair and recombination. BLM functions during replication stress and is required for the recruitment of several other important repair proteins including NBS1, BRCA1, Rad51 and MLH1. In addition, the BLM helicase is involved in recombinational repair events as evidenced by its ability to promote branch migrations of Holliday junctions at stalled replication forks. BLM may also play a role in apoptosis since it directly interacts with p53 and helps regulate its transcriptional activity."
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3.ATM gene
Ataxia telangiectasia mutated
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Ataxia telangiectasia mutated
Identifiers
Symbols ATM; AT1; ATA; ATC; ATD; ATDC; ATE; TEL1; TELO1
External IDs OMIM607585 MGI107202 HomoloGene30952 ChEMBL: 3797 GeneCards: ATM Gene
EC number 2.7.11.1
Orthologs
Species Human Mouse
Entrez 472 11920
Ensembl ENSG00000149311 ENSMUSG00000034218
UniProt Q13315 Q62388
RefSeq (mRNA) NM_000051 NM_007499
RefSeq (protein) NP_000042 NP_031525
Location (UCSC) Chr 11:
108.09 – 108.24 Mb
Chr 9:
53.44 – 53.54 Mb

PubMed search [1] [2]
Ataxia telangiectasia mutated (ATM) is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2 and H2AX are tumor suppressors.
The protein is named for the disorder Ataxia telangiectasia caused by mutations of ATM.[1]

GOLDGAR ET AL suggested:

"The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2."

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4. MRE 11 gene

MRE11A

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MRE11 meiotic recombination 11 homolog A (S. cerevisiae)
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MRE11A; ATLD; HNGS1; MRE11; MRE11B
External IDs OMIM600814 MGI1100512 HomoloGene4083 GeneCards: MRE11A Gene
RNA expression pattern
PBB GE MRE11A 205395 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4361 17535
Ensembl ENSG00000020922 ENSMUSG00000031928
UniProt P49959 Q61216
RefSeq (mRNA) NM_005590 NM_018736
RefSeq (protein) NP_005581 NP_061206
Location (UCSC) Chr 11:
94.15 – 94.23 Mb
Chr 9:
14.78 – 14.84 Mb

PubMed search [1] [2]
Double-strand break repair protein MRE11A is a protein that in humans is encoded by the MRE11A gene.[1]
This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms.[2]

Interactions

MRE11A has been shown to interact with Ku70,[3] Ataxia telangiectasia mutated,[4][5] MDC1,[6] Rad50,[3][5][7][8][9] Nibrin,[5][9][10][11][12] TERF2[13] and BRCA1.[5][7][14][15]

 FUKUDA ET AL

"MRE11, RAD50, and XRS2 have been identified in yeast as components of the HR and NHEJ pathways (4) . A physical complex with these proteins has been identified. In vertebrates, MRE11 and RAD50 form a complex with NBS1, whose mutation causes NBS (5 , 6) . The clinical features of NBS overlap with those of AT. They are characterized by chromosome instability, increased hypersensitivity to ionizing radiation, immunodeficiency, and predisposition to cancer. AT is caused by mutations in the ATM gene, which encodes a protein kinase homologous with phosphatidylinositol-3 kinase (7) . ATM is a key regulator of the cellular response to DSBs. NBS1 is phosphorylated in an ATM-dependent manner after ionizing radiation, suggesting a link between ATM and NBS1 in a common signaling pathway (8) . MRE11 phosphorylation upon DNA damage is dependent on NBS1 (9) . Therefore, it is highly likely that MRE11 participates in the same pathway in response to DNA damage. Consistent with this functional interaction, hypomorphic mutations in the MRE11 gene cause ataxia-telangiectasia-like disorder, the phenotypes of which are indistinguishable from those of AT (10) ."

 ATM mutations play a causal role in AT and have been demonstrated in lymphoid malignancies
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5.  RAD51
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RAD51 homolog (S. cerevisiae)

A filament of Rad51 based on PDB 1SZP.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols RAD51; BRCC5; HRAD51; HsRad51; HsT16930; MRMV2; RAD51A; RECA
External IDs OMIM179617 MGI97890 HomoloGene2155 GeneCards: RAD51 Gene
RNA expression pattern
PBB GE RAD51 205024 s at tn.png
PBB GE RAD51 205023 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5888 19361
Ensembl ENSG00000051180 ENSMUSG00000027323
UniProt Q06609 Q08297
RefSeq (mRNA) NM_001164269 NM_011234
RefSeq (protein) NP_001157741 NP_035364
Location (UCSC) Chr 15:
40.99 – 41.02 Mb
Chr 2:
119.11 – 119.15 Mb

PubMed search [1] [2]
"RAD51 is an eukaryote gene. The protein encoded by this gene is a member of the RAD51 protein family which assist in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA and yeast Rad51. The protein is highly conserved in most eukaryotes, from yeast to humans.
BRCA genes

This protein can interact with the ssDNA-binding protein RPA, BRCA2, PALB2[3] and RAD52.
The structural basis for Rad51 filament formation and its functional mechanism still remain poorly understood. However, recent studies using fluorescent labeled Rad51[4] has indicated that Rad51 fragments elongate via multiple nucleation events followed by growth, with the total fragment terminating when it reaches about 2 μm in length. Disassociation of Rad51 from dsDNA, however, is slow and incomplete, suggesting that there is a separate mechanism that accomplishes this."

"The RAD51 gene family, genetic instability and cancer.

Source

Medical Research Council, Radiation and Genome Stability Unit, Harwell, Oxfordshire OX11 0RD, UK. j.thacker@har.mrc.ac.uk

Abstract

Inefficient repair or mis-repair of DNA damage can cause genetic instability, and defects in some DNA repair genes are associated with rare human cancer-prone disorders. In the last few years, homologous recombination has been found to be a key pathway in human cells for the repair of severe DNA damage such as double-strand breaks. The RAD51 family of genes, including RAD51 and the five RAD51-like genes (XRCC2, XRCC3, RAD51L1, RAD51L2, RAD51L3) are known to have crucial non-redundant roles in this pathway."---------------------------------------------------------------------

THE BRCA ITSELF TO WORK NEED A BUNCH OF VARIOUS COFACTORS CALLED  FANCB-Related Fanconi Anemia, FANCC-Related Fanconi Anemia, FANCD2-Related Fanconi Anemia, FANCE-Related Fanconi Anemia, FANCF-Related Fanconi Anemia, FANCG-Related Fanconi Anemia, FANCI-Related Fanconi Anemia, FANCL-Related Fanconi Anemia, FANCM-Related Fanconi Anemia, PALB2-Related Fanconi Anemia, RAD51C-Related Fanconi Anemia, SLX4-Related Fanconi Anemia (ALTER ET AL!)

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