"DNA RecQ4 Helicase and the Effects of Rothmund-Thomson Syndrome"

- An Investigatory Report by Craig Oliver

Table of Contents

I. Helicase Basics

II. RecQ Helicase

III. Rothmund-Thomson Syndrome

IV. Treatment

I.  Helicase Basics

General Importance and Function

     -Helicases are a special class of proteins that are vital to all living things.  As enzymes, they function as motor proteins that participate in a variety of cellular processes.  As motor proteins, they move directionally along the phosphodiester bonds of nucleic acids.  They separate nucleic acid strands using the energy from ATP hydrolysis (wikipedia).

     -Such cellular processes as DNA replication, transcription, translation, recombination and DNA repair require the separation of nucleic acid strands.  These processes are most often used to separate strands of a DNA double helix utilizing the energy from ATP hydrolysis.  Helicases break the hydrogen bonds between complementary nucleic acid strands.  They move along a strand with a directionality and processivity that is specific for each type of the enzyme.  Since there are so many different roles for helicases in molecular biology, it is no surprise that there are many different kinds of helicases (wikipedia). 

Function and Structure

     -Helicases mostly have a common function and this accounts for a certain amount of amino acid sequence homologies and sequence motifs.  Sequence motifs are found in the interior of the primary sequence of a helicase.  They are involved in ATP binding, ATP hydrolysis, and translocation on nucleic acid substrates.  Amino acid sequence variations are related to the specific features of each particular helicase.  Since helicases have defined sequence motifs, researchers can attribute certain helicase activities to a given protein, even if the motif doesn't confirm the protein as a helicase.  However, these conserved motifs support a great degree of evolutionary homology among the enzymes, and thus helicases are separated into 4 superfamilies and 2 smaller families (wikipedia).

     -RecQ helicases are part of Superfamily 2 and are involved in genome maintenance and DNA replication (wikipedia).

II.  RecQ Helicase Basics

RecQ Helicase Family

     -RecQ helicases belong to the family of helicase enzymes that are responsible for genome maintenance.  These enzymes unwind DNA by catalyzing the hydrolysis of ATP, and are responsible for the 3' - 5' translocation in DNA.  The two main reactions that this family of enzymes drives are ATP + H2O --> ADP + Pi and NTP + H2O --> NDP + Pi.  They can in effect, unwind both DNA and RNA (Hyun et. al., Pubmedcentral) (wikipedia).

     -RecQ is responsible for plasmid recombination in Prokaryotes, as well as the repair of DNA damage from alkylating agents, free radicals, UV-light, and the reversal of damage due to replication errors.  In Eukaryotes, it's primary roles involve aging, silencing of genes, recombination, replication and DNA repair.  Without RecQ proteins, replication cannot occur in Eukaryotes because there would be no way to unwind the double-helix structure of DNA (wikipedia).

     -RecQ helicases are responsible for many human diseases.  There are at least five RecQ genes in the human genome.  Mutations in these genes are responsible for three heritable human diseases:  Werner Syndrome, Bloom Syndrome, and Rothmund-Thomson Syndrome.  These mutations cause characteristic symptoms in all three syndromes which include premature aging, type II diabetes, cancer, graying and hair loss, osteoporosis, and atherosclerosis.  All of these diseases are characteristic of someone of older age, and are associated with high occurrences of chromosome abnormalities such as breaks, rearrangements, deletions and translocations, site-specific mutations, and exchange of sister chromatids (wikipedia).

     -Properly functioning RecQ helicase enzymes interact with Topoisomerase III.  Topoisomerase III is an enzyme that changes the topological status of DNA.  It binds and cleaves single stranded DNA and passes either a single stranded or double stranded segment of DNA through the break.  The cleaved strand is then sealed by DNA ligase.  Topoisomerase III and RecQ helicase interactions suppress both spontaneous and damage induced recombination.  Without these interactions, an organism can inherit a deleterious phenotype.  This is all because the helicase enzyme and Topoisomerase III control recombination events, and repair DNA damage that arises during the G2-phase of the cell cycle.  They function to maintain genomic stability and integrity.  This is clearly seen by examining individuals who have mutations in their RecQ helicases.  Those with mutations do not have proper growth or development and the result is one of the syndromes listed previously (wikipedia).

An Animation of DNA Helicase General Activity

 III.  Rothmund-Thomson Syndrome

     -Rothmund-Thomson Syndrome is the result of a mutation in RecQ protein-like 4, which is commonly abbreviated as RecQL4 or RecQ4.  Rothmund-Thompson Syndrome is also known as Poikiloderma Congenitale.  It is an autosomal recessive disease that was first described in 1868 by August Von Rothmund, and was later described further in 1936 by Matthew Sydney Thompson (Wang and Plon, Gene Reviews).

     -The disease is characterized by abnormal rashes (called poikiloderma skin pigmentation), juvenile cataracts, congenital bone defects (such as short stature and radial ray anomalies), saddle nose, lack of eyelashes, eyebrows or hair, calcium problems, and ear problems.  Other problems include Telangiaectasia (small dilated blood vessels near skin surface or mucus membranes), Hypogonadism (lack of function in the gonads), Osteosarcoma (malignant bone cancer), and Hypodontia (fewer teeth than normal) (Wang and Plon, Gene Reviews).

     -Rothmund-Thomson Syndrome is a rare disease with only 300 cases reported worldwide.  Mutations in the RecQ4 gene are believed to be responsible for over 2/3 of reported cases.  The gene is responsible for making a protein that researchers believe helps stabilize genetic information in cells.  Not much is known about the protein but it is believed to be involved in DNA replication and repair.  Mutations in the gene produce an abnormally short and nonfunctional version of the RecQ4 protein and prevents cells from making the protein.  This shortage of the protein can prevent DNA replication and repair and consequently cause large amounts of damage to genetic information (medicine.net).

-  In 1/3 of cases of individuals with Rothmund-Thomson syndrome, there is is no mutation in the RecQ4 gene which leads scientists to believe that these cases result from mutations in a gene related to RecQ4 (medicine.net).

-  In some of the cases, chromosomal abnormalities such as extra or missing genetic material have been identified.  These abnormalities usually occur on chromosome 7 or 8.  These chromosomal changes are responsible for some of the instability of a person's genetic information (medicine.net).

A video showing a child with Rothmund-Thomson Syndrome

 IV.  Treatment

     -Treatment typically involves surgical removal of cataracts and the use of a pulsing dye to treat the telangiectatic component of the rash.  In addition, standard cancer treatment is employed for those who have developed signs or symptoms of cancer.  Patients have annual eye check-ups, screenings for osteosarcoma or other cancers, and general physical examinations.  Children with Rothmund-Thomson syndrome are often taken to a pediatrician, dermatologist, orthopedic surgeon, dental surgeon and other specialists.  Sun protection is extremely important due to the increased risk of skin cancer and photosensitivity (medicine.net) (Wang and Plon, Gene Reviews).

     -The goals of medication are to reduce morbidity and prevent complications.  Retinoids help reduce the potential for malignant degeneration.  Isotretinoin is an oral medication that treats the dermatologic conditions of the syndrome and is structurally related to vitamin A (Hsu and George, emedicine) (Wang and Plon, Gene Reviews).