Outline:

• RecQL3 Helicase
• The Genetics
• Mutations in RecQL3
• How is it caused?
• Bloom Syndrome
• Bloom Syndrome Foundation

 RecQL3 Helicase 

RecQ helicases play an important role in both prokaryotes and eukaryotes in maintaining the stability of DNA (Ellis et al.) as it is unwound for replication (Brosh et al.).  Below is an animation that shows the basics of DNA replication and the role that helicase plays in it.

RecQL3 is a 3-5' "RecQ-like" helicase involved in DNA replication.  The RecQL3 protein is one of five RecQ helicases that we know of.  The others are RecQL, WRN, RecQL4, and RecQL5 (Wu et al.). RecQL3 is primarily found in the nucleus of the cell and varies in concentration throughout the cell cycle.  It forms a ring structure like other helicases and is most prominent during the S phase in the nucleolus (www.davidson.edu). Specifically, it uses ATP to unwind all types of DNA and it is the only RecQ that can unwind strands that include four guanines in a row on ssDNA that double over onto each other forming kinks (Karow et al.). These are important to unwind for DNA metabolism to occur (Karow et al.).  It is also thought to be involved in double-strand break repair and it is also associated with promoting branch migration of holiday junctions (www.atlasofgenetics.com).  It has a function in telomere requlation as well (Zhou et al.) RecQL3 has also been shown to have a function in DNA fork repair (Bachrati and Hickson-1).  Also, it is hypothesized that RecQL3 is involved in suppressing sister chromatid recombination, as subjects with mutations in this gene show a huge increase in recombination (Karowet al.).

"Figure 2. Potential roles for RecQ helicases. (a) Disruption of recombination intermediates. RecQ helicases may promote Holliday junction branch migration. If this reaction were to proceed in the reverse direction, such an activity would result in the disruption of recombination intermediates and the subsequent restoration of parental chromosomes. Sister chromatids are depicted as black and grey. (b) Disruption of joint molecules. During recombination, the invading strand (grey) must become plectonemically wound around the complementary strand with the concomitant unlinking of the displaced strand. The strand passage activity of the combined actions of E. coli RecQ and topo III may act to disrupt such a joint molecule by unlinking regions of heteroduplex DNA and catalysing the relinking of the parental strands (black). (c) Disruption of G4-DNA. G-rich sequences may form G4-DNA during processes that involve unwinding of duplex DNA, such as transcription and replication. RecQ helicases may function to remove G4-DNA that could potentially pose a physical block to the progression of the replication machinery." (Karow et al.).

 The Genetics

The gene that codes for the RecQL3 protein is the Bloom Syndrome gene located on the long arm of Chromosome 15 (German et al.) (Puranum,et al.).  Here is an image of the entire gene (www.davidson.edu).

(www.davidson.edu)

Below is an image of various genes in the RecQ helicase family, which are highly conserved from bacteria to humans in evolutionary history (Kahkahr et al.).  They all include the helicase genes which are shown in black and the length and relatedness is shown on the right.

(Kahkahr et al.)

Mutations in RecQL3

Mutations in RecQL3 cause a decrease in genetic stability (Hanada and Hickson).  This causes hyperrecombinability (OMIM-RecQL3) and problems in cell division throughout the persons life, which is of course linked to cancer at an early age and also causes infertility (OMIM-RecQL3).  In fact, any mutation found in the RecQ helicases leads to a disease that is linked to a predisposition to cancer.  These include Werner, Bloom, Rothmund-Thomson, RAPADALINO, and Baller-Gerold syndromes (Nakayama et al.)(Bachroti and Hickson-2).   The disorder most commonly tied to mutations in the RecQL3 protein is Bloom Syndrome, which gives it the name the Bloom Syndrome Protein 

(OMIM-BLM).

How is it caused?

Bloom Syndrome is an autosomal recessive disorder that is found predominantly in Ashkenazi Jews and people of Japanese inheritance (www.atlasofgenetics.com). The gene mutation interferes with the DNA replication stage. Studies show that when helicase encounters a DNA strand that slows replication, the BLM protein is recruited to the area by Pol  (Selak, Nives et al. 2008) and involved in causing double stranded breaks in the chromosomes (Shimura, Tsutomu et al. 2007).  It can also interfere in recombination causing an increased rate of sister chromosome change  (www.atlasofgenetics.com) possibly by causing inefficient peroxide removal from cells (www.emedicine.com).  Below is an image of a normal recombination event (left) compared to one in cells with the mutation (right).

(www.atlasofgenetics.com) 

 Bloom Syndrome

Bloom Syndrome is a disease that affects 1 in every 48,000 people (www.geneticshome.com).  It causes men to not produce sperm and it causes women to go through menopause early.  It also causes lung problems, dwarfism, itellectual disorders, sun sensitive skin, cancer predisposition, diabetes, and immune deficiencies that lead to recurrent problems such as pnemonia (Kusano et al.) (www.symptoms.com).  People with Bloom Sydrome are more predisposed to all different kinds of cancers and it eventually it leads to death before the age of thirty.  One of the more apparent symptoms of Bloom Syndrome is that it causes butterfly shapped red patches to appear on the skin (www.symptoms.com).

(www.geneva.com)

(www.geneva.com)

To learn about how you can support the research about Bloom Syndrome you can visit the

Bloom Syndrome Foundation website and learn about how you can support the research on prevention and therapy.