Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome. [5]
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. [6]
Recombination during meiosis is often initiated by a DNA double-strand break (DSB). During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken. After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination and bottom of Figure in this section).
The budding yeast Saccharomyces cerevisiae encodes an ortholog of the Bloom syndrome (BLM) protein that is designated Sgs1 (Small growth suppressor 1). Sgs1(BLM) is a helicase that functions in homologous recombinational repair of DSBs. The Sgs1(BLM) helicase appears to be a central regulator of most of the recombination events that occur during S. cerevisiae meiosis. [7] During normal meiosis Sgs1(BLM) is responsible for directing recombination towards the alternate formation of either early NCOs or Holliday junction joint molecules, the latter being subsequently resolved as COs. [7]
In the plant Arabidopsis thaliana , homologs of the Sgs1(BLM) helicase act as major barriers to meiotic CO formation. [8] These helicases are thought to displace the invading strand allowing its annealing with the other 3’overhang end of the DSB, leading to NCO recombinant formation by a process called synthesis dependent strand annealing (SDSA) (see Genetic recombination and Figure in this section). It is estimated that only about 4% of DSBs are repaired by CO recombination. [9] Sequela-Arnaud et al. [8] suggested that CO numbers are restricted because of the long-term costs of CO recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection.
Bloom syndrome protein facilitates DNA repair when cells are stressed by agents that cause DNA damage, specifically when DNA replication forks are stalled. Damage present during S phase of the cell cycle causes Bloom syndrome protein to rapidly form foci with gamma H2AFX protein at replication forks that develop DNA breaks. [10] These BLM foci then recruit repair complexes composed of BRCA1 and NBS1 proteins to the stalled replication forks. In addition to its role in repairing DNA damages, Bloom syndrome protein facilitates apoptosis (programmed cell death), a process dependent on p53 protein when cells are stressed by agents that cause unrepairable DNA damage, particularly damage that causes stalled DNA replication forks. [10] [11]
Both DNA repair and apoptosis are enzymatic processes necessary for maintaining genome integrity in humans. Cells that are deficient in DNA repair tend to accumulate DNA damages, and when such cells are also defective in apoptosis they tend to survive even though excessive DNA damage is present. [12] Replication of DNA in such cells tends to lead to mutations and such mutations may cause cancer. Thus Bloom syndrome protein appears to have two roles related to the prevention of cancer, where the first role is to promote repair of a specific class of damages and the second role is to induce apoptosis if the level of such DNA damage is beyond the cell's repair capability [12]
Bloom syndrome protein has been shown to interact with:
Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two hybridized nucleic acid strands, using energy from ATP hydrolysis. There are many helicases, representing the great variety of processes in which strand separation must be catalyzed. Approximately 1% of eukaryotic genes code for helicases.
RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.
Bloom syndrome is a rare autosomal recessive genetic disorder characterized by short stature, predisposition to the development of cancer, and genomic instability. BS is caused by mutations in the BLM gene which is a member of the RecQ DNA helicase family. Mutations in genes encoding other members of this family, namely WRN and RECQL4, are associated with the clinical entities Werner syndrome and Rothmund–Thomson syndrome, respectively. More broadly, Bloom syndrome is a member of a class of clinical entities that are characterized by chromosomal instability, genomic instability, or both and by cancer predisposition.
Werner syndrome ATP-dependent helicase, also known as DNA helicase, RecQ-like type 3, is an enzyme that in humans is encoded by the WRN gene. WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double-stranded DNA. These activities are necessary before DNA can be copied in preparation for cell division. Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called transcription. Further evidence suggests that Werner protein plays a critical role in repairing DNA. Overall, this protein helps maintain the structure and integrity of a person's DNA.
XPB is an ATP-dependent DNA helicase in humans that is a part of the TFIIH transcription factor complex.
A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.
DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. The gene is commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.
Ku80 is a protein that, in humans, is encoded by the XRCC5 gene. Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. It is also required for V(D)J recombination, which utilizes the NHEJ pathway to promote antigen diversity in the mammalian immune system.
Replication protein A 70 kDa DNA-binding subunit is a protein that in humans is encoded by the RPA1 gene.
DNA replication licensing factor MCM2 is a protein that in humans is encoded by the MCM2 gene.
DnaJ homolog subfamily A member 3, mitochondrial, also known as Tumorous imaginal disc 1 (TID1), is a protein that in humans is encoded by the DNAJA3 gene on chromosome 16. This protein belongs to the DNAJ/Hsp40 protein family, which is known for binding and activating Hsp70 chaperone proteins to perform protein folding, degradation, and complex assembly. As a mitochondrial protein, it is involved in maintaining membrane potential and mitochondrial DNA (mtDNA) integrity, as well as cellular processes such as cell movement, growth, and death. Furthermore, it is associated with a broad range of diseases, including neurodegenerative diseases, inflammatory diseases, and cancers.
Growth arrest and DNA-damage-inducible protein GADD45 alpha is a protein that in humans is encoded by the GADD45A gene.
Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.
DNA repair protein RAD51 homolog 4 is a protein that in humans is encoded by the RAD51L3 gene.
DNA repair protein XRCC2 is a protein that in humans is encoded by the XRCC2 gene.
DNA topoisomerase 3-alpha is an enzyme that in humans is encoded by the TOP3A gene.
RecQ-mediated genome instability protein 1 is a protein that in humans is encoded by the RMI1 gene.
Sgs1, also known as slow growth suppressor 1, is a DNA helicase protein found in Saccharomyces cerevisiae. It is a homolog of the bacterial RecQ helicase. Like the other members of the RecQ helicase family, Sgs1 is important for DNA repair. In particular, Sgs1 collaborates with other proteins to repair double-strand breaks during homologous recombination in eukaryotes.
DNA polymerase delta subunit 4, also known as DNA polymerase delta subunit p12, is a protein that in humans is encoded by the POLD4 gene. It is a component of the DNA polymerase delta complex.
Stephen Charles Kowalczykowski is a Distinguished Professor of Microbiology and Molecular Genetics at the University of California at Davis. His research focuses on the biochemistry and molecular biology of DNA repair and homologous recombination. His lab combines fluorescence microscopy, optical trapping and microfluidics to manipulate and visualize single molecules of DNA and the enzymes involved in processing and repairing DNA. He calls this scientific approach, "visual biochemistry". Stephen Kowalczykowski was elected to the American Society for Arts and Science in 2005, the National Academy of Sciences in 2007 and was a Harvey Society Lecturer at Rockefeller University in 2012.
| Excision repair | |
|---|---|
| Homologous recombination | |
| Other pathways | |
| Regulation | |
| Other/ungrouped | |
